Hindawi Publishing CorporationISRN Cell BiologyVolume 2013 Article ID 126731 15 pageshttpdxdoiorg1011552013126731

Review ArticleIntra-Golgi Transport Roles for Vesicles Tubules and Cisternae

Joseacute A Martiacutenez-Menaacuterguez

Department of Cell Biology and Histology Medical School University of Murcia 30100 Murcia Spain

Correspondence should be addressed to Jose A Martınez-Menarguez jamartinumes

Received 17 December 2012 Accepted 7 January 2013

Academic Editors J C Hay R Puertollano T Yazawa and Y Zhang

Copyright copy 2013 Jose A Martınez-MenarguezThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in anymedium provided the originalwork is properly cited

TheGolgi complex is considered the central station of the secretory pathway where cargo proteins and lipids are properly modifiedclassified packed into specific carriers and delivered to their final destinations Early electron microscope studies showed theextraordinary structural complexity of this organelle However despite the large volume of incoming and outgoing traffic it isable to maintain its architecture although it is also flexible enough to adapt to the functional status of the cell Many componentsof the molecular machinery involved in membrane traffic and other Golgi functions have been identified However some basicaspects of Golgi functioning remain unsolved For instance how cargo moves through the stack remains controversial and twoclassical models have been proposed vesicular transport and cisternal maturation Since neither of these models explains all theexperimental data a combination of these models as well as newmodels have been proposed In this context the specific role of thecisternae vesicles and tubules needs to be clarified In this review we summarize our current knowledge of the Golgi organizationand function focusing on the mechanisms of intra-Golgi transport

1 Introduction

Eukaryotic cells are highly compartmentalized in organelleswhich are surrounded by membranes Every compartmenthas its own composition structure and function Howeverthese elements are not totally isolated because there is a con-tinuous flow of components between them Endocytic andsecretory routes are complex processes involving formationmovement and fusion with the specific targets of transportcarriers Palade was a pioneer in this field by establishingthat newly synthesized proteins in the endoplasmic reticulum(ER) move to the Golgi complex (GC) and they are packedin secretory granules before being secreted [1] Although thisconcept is a dogma in cell biology some proteins bypassthe GC on their way to the cell surface a process known asunconventional trafficking [2] The central role of the GC inthe secretory pathway is nowadays understood [3 4] TheGC receives newly synthesized proteins and lipids from theER This cargo is classified packed and delivered to the finaldestination but is extensively modified on the way mainlyinvolving the glycosylation of proteins and lipids Recently akey role in many cellular processes has been associated withthis compartment including microtubule nucleation signal-ing and calcium homoeostasis [5] In recent decades the

molecular machinery involved in many of these processeshas been identified Progress in the field is directly relatedwith the application of new methodologies such as livecell imaging [6ndash8] organelle proteomics [9 10] functionalgenomics [11] high-resolution immunocytochemistry [1213] correlative light-electron microscopy [14] and electrontomography [15] However despite the huge amount ofdetailed information available there are still many questionsopened and some basic principles remained to be completelyunderstood This paper presents an overview of Golgi orga-nization focusing on the mode of intra-Golgi transport Fordetails of the topic treated in this paper and other aspects ofGolgi function such as post-GolgiTGN transport signalingstructure in lower organisms or behavior during cell deathand division many excellent reviews can be consulted [5 16ndash24]

2 Golgi Organization

Under electron microscopy the GC can be unambiguouslyidentified from its singular appearance It is usually composedof 3ndash9 stacked flat cisternae forming the Golgi stack ordictyosome surrounded by tubulovesicular elements [25ndash27]

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Figure 1 Cryosection of the Golgi complex of rat exocrine pan-creatic cells Typical image of a cross-sectioned Golgi complex 1 =endoplasmic reticulum exit site 2 = tubulovesicular elements associ-ated to ERGIC 3 = tubularmembranes associatedwith theCGN 4 =stack of cisternae 5 = TGN elements 6 = secretory granule Bar =200 nm

(Figures 1 and 2) The stack of cisternae is considered thecentral domain of the GC Cisternae are very narrow in thecenter and dilated at the lateral rims where they show coatedbuds The low areavolume ratio favors interaction betweenthe enzymatic machinery of membranes and the cargo Theyoften show fenestrations sometime appearing as large holesthat formwells [28]Themorphology of the stacked cisternaedepends on the cargo Thus when protein synthesis isblocked the cisternae are very thin and stacks show an onion-like organization [29]The pH is also important and a low pHinduces thin cisternae [30] In most mammalian cells Golgistacks are laterally connected to form continuous ribbonThe reason for this not known but could be related withadvanced functions such as polarized secretion cell motil-ity and signalling [31 32] The maintenance of the Golgiribbon depends on the microtubular cytoskeleton and abalanced inward and outward transport Microtubule de-polymerization induced bynocodazole breaks the ribbon intoministacks [33] a process that is reversible demonstratingthat the GC is a high dynamic organelle Interestingly theGolgi ribbon appeared fragmented into ministacks in manyneurological diseases including Parkinsonrsquos disease [16 3435] The lateral area of the stacks where one connects withanother is known as the noncompact region This shows acomplex morphology and is filled with vesicles and otherheterogeneous elements [36]

The composition of the cisternae is not homogeneous andit contains different sets of resident proteins Based on thisGolgi stacks have been classically divided into cismedial andtrans sides Cis cisternae receive newly synthesized proteinsand lipids from the ER while cargo exits the organelle atthe trans side taking 10ndash20 minutes to traverse the stack ERelements tightly associated with the transmost cisternaehave been described the role of which is not known butmay be related with the direct transfer of lipids between

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Figure 2 Cryosection of the Golgi complex of a rat exocrinepancreatic cell Face view of a single cisterna (G) showing the hugecomplexity of the surrounding tubulovesicular elements (asterisk)Without a detailed immunocytochemical analysis of their composi-tion and high-resolution structural study it is not possible to discernwhether these membranes represent the ERGIC CGN peri-Golgivesicles or tubules connecting the stacks laterally N=nucleus Bar =200 nm

these organelles [28] The primary role of the stack is theglycosylation of proteins and lipids In the GC there areglycosidases nucleotides sugar transporters and at least 200different glycosyltransferases [37] few of which are homo-geneously distributed through the Golgi stack For exam-ple enzymes associated with early and late steps of gly-cosylation are predominantly found at the cis and transsides respectively Peptide-GalNAc-transferase and GlcNAc-phosphotransferase are associated with the cis Golgi man-nosidase I and II GlcNAc transferase I and phosphodi-esterase to the medial Golgi and 120573-14-galactosyltransferaseand 120572-26-sialyltransferase to the trans side [38] Most pro-teins associated with the Golgi function (matrix proteinsRabs SNARE etc) also show a polarized distributionThere isalso a cis-trans gradient of cholesterol and sphingolipids [3940] The retention of transmembrane proteins within Golgimembranes depends on protein-protein interactions thecomposition and length of the transmembrane domain andcytoplasmic tail the lipid environment and their bind-ing affinity to coat complexes whereas the localization ofperipheral membrane proteins depends on protein-proteininteraction and the posttranslational addition of lipids [41]It should be noted that such polarization is not strict butrather proteins show a gradient-like distribution suggestinga dynamic equilibrium Supporting this concept the locationof N-acetylgalactosaminyl transferase the enzyme that initi-ates O-glycosylation is regulated by growth factors that caninduce its redistribution to the ER [42]

Associated to the cis Golgi side of the Golgi stack thereis a tubulovesicular system known as the cis-Golgi network(CGN)This is formed of tubules connected to the first Golgicisterna [43ndash46] a cisterna containing many fenestrations[28] In early electron microscopical studies these tubuleswere selectively stained with reducing osmic for prolongedtimes The boundaries and the functional relationship of this

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tubular network connected to the stack and ER-derived pre-Golgi tubule-vesicular elements (see below) remain to beestablished

The trans-Golgi network (TGN) is located at the transside and is the place where proteins are sorted packed anddelivered to their final destination (endolysosomal systemapical or basolateral membranes secretion) It is also thecompartment where secretory and endocytic routes converge[47] In the TGN the final steps of glycosylation (includingsulfation and sialylation) serine-linked O-phosphorylationand the proteolytic processing of hormone precursors takeplace The organization of these membranes depends on celltype Usually the TGN is formed by a network of tubulo-vesicular membranes connected to one or two transmostcisternae while secretory cells containing immature secre-tory granules However the TGN may be an independentcompartment adjacent to the stack or conversely at somedistance from the same [48ndash51] The tubular component isextensive in cells with a well-developed lysosomal system andreduced in secretory cells The structural variability of theTGN may be due to its capacity to secrete different types ofcargo [52] and it is not clear whether this compartment isdivided into subdomains representing specialized exit sitesfor different destinations [22 53 54] Although function-ally and structurally connected the TGN and Golgi stackare different compartments as demonstrated in the use ofbrefeldin A This fungal drug induces the tubulation of bothcompartments but fusion with the endosomal system or ERrespectively [55] The pH of the TGN is more acidic than themedialtrans cisternae (658 and 591 resp) [56]

The structure of the GC is supported by the so-calledGolgi matrix a ribosome-free area surrounding the cisternaeand formedby structural proteinsThismatrix is visualized byelectron microscopy as small fibers connecting the cisternae[57] and also connecting the Golgi membranes and transportvesicles [58] A large number of Golgi matrix componentshave been identified including Golgi reassembly stackingproteins (GRASPs) and golgins [59] with GM130 being thefirst component identified [60] Some of the componentswere identified as autoantigens and others were isolated fromdetergent-insoluble salt-resistant Golgi fractions [61] Thesecomponents are very dynamic and cycle betweenmembrane-associated and a cytoplasmic forms process that dependson posttranslational modifications such as phosphorylationMatrix proteins are involved in the regulation of membranetraffic and the maintenance of the Golgi structure Morerecently the matrix has been related to microtubule organi-zation signaling and regulation of apoptosis and cell cycle[59]

The organization of the Golgi ribbon also depends onthe microtubule and actin cytoskeleton [62 63] In non-polarized cells stacks are distributed around the microtubuleorganization center (MTOC) usually close to the nucleus[64 65] However microtubules are not essential for otherfunctions such as glycosylation or global secretion Thefinal position of the ribbon and transport into or from thisorganelle is determined by the action of molecular motorsThemovement of transport carriers from the periphery to theGC at the cell centre is mediated by the minus-end-directed

motor dynein This motor and its cofactor dynactin areessential for maintenance of the perinuclear position of theGolgi ribbon [66] The movement in the opposite directionis mediated by the plus-ended-directed motor kinesin Inter-estingly the GC is able to nucleate and stabilize microtubulesacting as a secondary MTOC [67] The cis-Golgi proteinGMAP210 recruits 120574-tubulin to this organelle AKAP450 a 120574-tubulin-interaction centrosomal protein is also found at theGolgi after recruitment by GM130 [68] At the trans-Golgithe nucleation of microtubules depends on microtubule-binding proteins CLASPs which are recruited to the Golgimembranes through the golgin GCC185 [69] This processis necessary for polarized secretion and the maintenanceof the Golgi ribbon [70] On the other hand actin hasbeen associated with coated transport vesicles and buds [71]Golgi membranes also contain molecules such as Arp23N-WASP or cdc42 that trigger actin polymerization [72]Actin filaments and actin-associated proteins are involved inpost-Golgi [73] andGolgi-to-ER [74] transport Interestinglythe action of the microtubule and actin cytoskeletons iscoordinated [75] One of the factors involved in this link is theprotein WHAMM (WASP homology associated with actinmembrane and microtubules) which is present in the Golgiand pre-Golgi elements This protein has domains that bindactin-binding proteins such as profilin andArp23 a domainthat directly bind microtubules and a domain required tobind lipids [76] WHAMM regulates carrier morphologyduring intracellular transport [77]

3 Transport Carriers Vesicles

The stacks are surrounded by small vesicles of different sizesand many of them are coated For example in two adjacentstacks of NRK cells of the sim400 vesicles found one halfwere coated [28]Three different types of coat complexes havebeen identified and characterized in detail (COPI COPIIclathrin) although the existence of other coat complexescannot be rejected

Clathrin-coated vesicles were the first to be identified [7879] Both their size (100 nm) and the coat thickness (18 nm)are larger than in COP vesicles [80] Clathrin is mainlyinvolved in transport fromGCor from the plasmamembraneto the endolysosomal system [81] In the Golgi area clathrin-coated vesicles and buds are associated with the trans-mostGolgi cisterna and TGN [28] where it is involved in theexport of mannose-6-phosphate receptors carrying newlysynthesized lysosomal enzymes [82] Clathrin is a proteincomplex formed by three heavy and three light chains thatassemble to make a basket-like structure made up of pen-tagons and hexagons [83]Their association with membranesand the recruitment of cargo is mediated by adaptor com-plexes Clathrin binds a variety of adaptor complexes involvedin different transport events In humans four ubiquitouslyexpressed adaptor complexes (AP1-4) and three Golgi-localized 120574-ear-containing ARF-binding proteins (GGA1-3)have been identified AP2 is restricted to the plasma mem-brane where it is involved in endocytosis whereas GGAsand AP1-4 are located at the TGN andor in endosomes [17]At theTGNAP1 andCGAproteins recognize specific signals

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present in mannose-6-phosphate receptors and contribute tothe sorting of these receptors which their cargo hydrolysesinto clathrin-coated vesicles [82] AP1 AP3 and AP4 (in thiscase independently of clathrin) are involved in the sortingof lysosomal membrane proteins at the TGN In polarizedcells AP1 AP3 and AP4 are involved in the sorting of baso-lateral membrane proteins but probably through a clathrin-independent mechanism [84] The binding of cargo andadaptor recruits clathrin which provides the scaffold for theinvagination of the membrane forming a coated pit Fissionof the vesicle requires the activity of the GTPase dynamin[85] whereas vesicle uncoating depends on recruitment ofthe chaperone Hsc70 by the nerve-specific auxilin or theubiquitous GAK [86]

COPII- and COPI-coated vesicles are morphologicallyvery similar They are 50ndash60 nm in diameter with a 10 nm-thick coat However their composition location and role intransport differ The COPII coat is formed of five proteinsSec23 Sec24 Sec13 Sec 31 and the GTPase Sar1 [87 88]These proteins are soluble in the cytosol but associated toform coated buds at the ER Sar1 is the first componentrecruited in ER membranes This binding depends on theactivation of this GTPase by Sec12 a guanine nucleotideexchange factor (GEF) present in ER membranes [89] Sar1recruits the Sec23Sec24 heterodimer and then the Sec13Sec31 complex [90] During this process some proteins areselectively recruited in COPII vesicles [91] whereas othersenter unspecifically a process known as bulk flow [92] Thesize of the COPII vesicles can be adapted to a bulky cargoTANGO 1 is an adaptor protein that helps collagen VII toenter into vesicles [93] Recently it has been shown that ubiq-uitination of Sec31 regulated the formation of large COPIIvesicles [94] The role of COPII in ER-to-Golgi transport iswell established In specific places of the ER the ER exit sitesthis coat complex drives the formation of free coated vesiclescontaining cargoThese are quickly uncoated and fuse to eachother to form the so-called endoplasmic reticulum-Golgiintermediate compartment (ERGIC) or vesicular-tubularaggregates (VTCs) [95] This compartment is formed oftubulovesicular elements located close to the GC and dis-tributed throughout the cell and is associated to ER exit sites[96] This compartment was initially identified because thecargo accumulated in these elements when cells are culturedat low temperature (15∘C) [97 98] At the ERGIC the COPIcoat mediates the recycling of proteins back to the ER whileanterograde cargo is separated and concentrated It is notclear whether the ERGIC is a stable and static compartmentor conversely whether it works as a carrier [99] The factthat the proteins associated with this compartment are notresident but cycling between the ER and Golgi argues againstthe idea that it is a stable compartment This is the casewith ERGIC-53 a type I transmembrane protein of the lectinfamily which is the prototypical marker of this compartment[100] Anyway ERGIC elements or ERGIC-derived carriersmove to theGolgi area along themicrotubule track and therethey may fuse to each other to form the CGN or converselyfuse with a preexisting cisterna [101]

COPI-coated vesicles are found in peripheral and cen-tral ERGIC elements cis and lateral Golgi sides [80] and

occasionally at the trans-Golgi sideTGN [102] COPI-coatedbuds are observed at the lateral rims of cisternae decreasingin number in a cis to trans direction [28] COPI and clathrin-coated areas have been observed in immature secretorygranules [92] The function of the COPI coat in the Golgi-to-ER retrograde transport of soluble and membrane pro-teins has been convincingly demonstrated [103] Howeverthere are retrograde routes to the ER independent of COPI[104] COPI has also been associated with the anterogradeand retrograde intra-Golgi transport of cargo and residentenzymes respectively although this role remains highly con-troversial (see below) COPI coats are also involved in Golgifragmentation duringmitosis Golgi positioning lipid home-ostasis and endocytic routes [105] It is possible that thereare several subpopulations of COPI vesicles with differentcompositions and locations each carrying out its specificfunctions [106] The discovery and characterization of COPIvesicles data from the early 1980s when transport intermedi-ates were analyzed in cell-free experiments incubatingGolgi-enriched membranes with cytosol and GTP120574S [107 108]COPI coats are formed of seven subunits (120572 120573 1205731015840 120574 120575 120576120577-COP) assembled in the cytosol where they form a complexnamed coatomer [109] and the small GTPase ARF1 [110]ARF1 cycles between GDP- and GTP-bound forms [111]GTP-bound ARF1 binds to membranes and recruits thecoatomer en bloc resulting in membrane deformation Likeall small GTPases the activity of ARF1 is regulated by guaninenucleotide exchange factors (GEPs) and GTPase-activatingprotein (GAP) GEF catalyzes the exchange ofGDPwithGTPGolgi-associated BFA-resistant protein (GBF1) is the majorGEF for ARF1 during COPI vesicle formation in the Golgimembranes and is the target of the drug brefeldin A [112 113]Brefeldin A blocks the ARF1-GEF complex inhibiting theformation of ARF1-GTP and triggering Golgi disassemblyARFGAP proteins stimulate the GTP hydrolysis of ARFwhich has low intrinsic GTPase activity [114] It has beenpostulated that this reaction triggers uncoating [115] butthis point is under discussion [116] The proteins BARS andendophilinB seem to be necessary for the fission of COPIvesicles Interestingly ARFs have a role in the recruitmentand activation of lipid-modifying enzymes In additionARFGAP1 the first identified GAP for ARF1 is a membranecurvature sensor [117] Cargo inclusion requires GTP hydrol-ysis [118] For cargo sorting coatomer recognizes dibasicsequences [105 119] Many transmembrane proteins trans-ported into COPI vesicles bear dilysine motifs at their C-terminus [120] including ERGIC-53 [121] The coatomersubunits 120572- and 1205731015840-COP bind this signal directly [122] Thep24 family of proteins (23-24 kD transmembrane proteins)are recruited by direct interaction of their cytoplasmic tailwhich contains phenylalanine- and dilysine-based signals tocoatomer [123] However not all cargo incorporated in COPIvesicles have this sorting signal and may require adaptorsOne example is the KDEL receptor a transmembrane proteinmostly present in the cis Golgi and ERGIC that works as anadaptor for soluble proteins It interacts with the coatomerthrough a dilysine motif in the cytosolic tail whereas theluminal part interacts with soluble proteins bearing a K-D-E-L sequence (HDEL in yeast) a sequence found in many

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ER-resident proteins [124 125] In this way soluble proteinsthat have escaped from the ER are retrieved Glycosylationenzymes may also require cargo adaptors [105]

4 Transport Carriers Tubules andHeterogenic Elements

For a long time it was assumed that membrane traffic ismediated by coated vesicles Although they play a key role inmany steps of the transport it is possible that coated vesiclesjust represent a fraction of the intermediate transport carriersoperating in the secretory pathway [126] Tubular elementson the other hand have been associated with all steps ofthe secretory pathway (Polishchuk and Mironov [52]) Thetransport of soluble [127] and transmembrane [99] cargofrom pre-Golgi elements to the Golgi is mediated by tubulesTubules are 20 of the elements operating at the ER-Golgiinterface [128] Post-Golgi carriers may also have a tubularform [129 130] In fact the TGN itself is often formed by anetwork of branching tubules

Tubules are also involved in intra-Golgi transport TheGC is associated to an extensive network of 30 nm-thicktubules connected to the lateral edges of the stacked cisternaeand may extend a considerable distance from the stacks [57]Golgi tubules were already observed in the first electronmicroscopical observations of this organelle [25] Early stud-ies showed tubular elements emerging from the Golgi stackand TGN connected to cisternae or oriented towards thecytoplasm [26 27] Hermo and coworkers [131] describedtubular connections between cisternae in the cis side of theGolgi apparatus of spermatids Despite this tubules werealmost forgotten in the field for decades probably due tothe difficulty of identifying them in bidimensional electronmicrographs (they only can be identified in longitudinalsections) This was exacerbated cisternal maturation modelbeing abandoned in favor of the vesicular transport modelResearch into these elements increased with the introductionof the drug brefeldin A in the study of the GC This druginduces extensive tubulation of this organelle Although thissystem is artificial it has been postulated that brefeldinA exaggerates the natural process of retrograde transportHowever in contrast with normal conditions this transportoccurs only after the dissociation of COPI coats from theGC The development of new methodologies such as time-lapse confocal microscopy or electron tomography hasreintroduced the idea that tubules are transport intermedi-ates Time-lapse analysis of living cells has shown tubulesemerging from the GC [132] containing GFP-tagged residentenzymes [133] or cargo [101 134] Electron tomography con-firms that these elements are commonly associated to theGC [28 135] In NRK cells there are tubules that emergefrom cis and trans cisternae suggesting that they are involvedin incoming and outgoing Golgi trafficking Tubules maygrow from all cisternae and may extend towards CGN andTGN Interestingly one single cisterna may contain tubulesoriented to both cis and trans faces [28] In cells stimulatedto increase the secretion rate tubular connections betweencisternae are evident [136 137] but these connections

disappear when cargo has left the GC Thus tubules mightreplace vesicles when there is an excess of cargo Tubules mayalso participate in the recycling of Golgi resident enzymesUnder low temperature (15∘C) conditions many tubulesemerge from theGC ofHeLa cellsThese tubules are enrichedin Golgi-resident enzymes and a specific set of SNAREand Rab proteins associated with intra-Golgi transport andcontain neither retrograde nor anterograde cargo [138 139]This type of tubule can also be observed under physiologicalconditions and they are good candidates for being consideredtransport intermediates at the Golgi level Several types oftubules with different functions may well exist

The molecular machinery involved in the formation ofGolgi tubules is just beginning to be known Based onbrefeldin A experiments tubular formation at the GC hasbeen related with the loss of COPI coats [140 141] GTP-bound ARF1 is able to induce Golgi tubules by insertion ofthe amino-terminal amphipathic helix [142] Microtubule-associated motor proteins are sufficient to induce tubulesfrom Golgi membranes [143] Some lipidic species such asphosphatidic acid diacylglycerol and lysophosphatidic acidfavor the curvature of membranes Thus enzymes associatedwith lipid metabolism play a key role in tubular formationLysophosphatidic acid generated by the enzyme phospho-lipase A2 has been involved in the retrograde transportmediated by tubules [144 145] Agonist and antagonist of thisenzyme increase or inhibit tubular formation respectivelyThis enzyme is involved in the formation of tubular continu-ities between cisternae [146] and tubular transport interme-diates at the TGN [147] The formation of transport carriersat the TGN is also diacylglycerol dependent This lipid isnecessary to recruit protein kinaseD a regulator of the fissionof transport carriers [54 148] Diacylglycerol has also beeninvolved in Golgi-to-ER retrograde transport mediated bytubules [149] Phosphatidic acid has been involved in intra-Golgi transport [150] Interestingly two lipid-modifyingenzymes lysophosphatidic acid acyltransferase-120574 and phos-pholipase A2-120572 which promote or inhibit COPI fissionrespectively work together regulating the morphology ofGolgi carriers [151] On the other hand the morphology ofpre-Golgi tubules depends on the cargo [128] COPI coatsmicrotubules and associated motor proteins [152] and alsothe activity of ARF and phospholipase A2 [153]Thus similarmachineries may be operating at different levels of the secre-tory pathway Interestingly live cell imaging shows that pre-Golgi elements may change their morphology very quicklyfrom vesicular to tubular form and vice versa [152]

Apart from the tubules other transport intermediates ofheterogeneous morphology have been described Polishchukand coworkers [154] described the formation of large tubulo-saccular elements involved in the microtubule-dependenttransport from the TGN to the plasma membrane The samegroup has described heterogenic membranes involved in ER-to-Golgi transport [155] Very large pleiomorphicmembrane-bound elements have also been associated with transportin the early secretory pathway [156] It seems that thereare different classes of transport carriers depending of theamount or type of cargo

6 ISRN Cell Biology

5 Molecular Machinery

In recent decades a huge amount of information has beenaccumulated about the molecular machinery involved inthe regulation of the intercompartmental transport in thesecretory pathway Most data refer to vesicles as transportcarriers but it can be assumed that the same or similar mech-anisms operate for other carriers If the formation of vesiclesand the selection of cargo depends on the coatmachinery thespecific targeting and fusion of the carriers with the targetmembranes depends on tethering factors Rab and SNAREproteins and other accessory proteins [157] In a simplemodel the rabs on incoming vesicles recruit tethering factorswhich permits SNARE complex formation

SNAREs (soluble N-ethylmaleimide-sensitive factorattachment proteins receptors) proteins are involved indocking and the specific fusion of transport intermediateswith the targetmembranes [157ndash159]The SNAREs associatedwith vesicles (or other transport intermediates) and targetmembranes have been named v- and t-SNARE respectivelyThis terminology however is not useful for describinghomotypic fusion events Structurally SNAREs have beendivided into R- and Q-SNAREs according to the centralresidue (RGln or QArg resp) of the SNARE domain aconserved region of 60ndash70 residues found in all members ofthis family Although there are some exceptions v-SNAREand t-SNARE are R-SNARE and Q-SNARE respectivelyInteraction between one v-SNARE and twothree t-SNAREinduces the formation of the trans-SNARE complex whichcatalyzes the fusion of the membranes SNARE proteins aresufficient to drive membrane fusion so that they are con-sidered the minimal membrane fusion machinery Afterfusion a cis-SNARE complex is formed in the target mem-branes This complex is later disassembled by the action ofthe cytosolic proteins 120572-SNAP (soluble N-ethylmaleimide-sensitive factor attachment protein) and the ATPase NSF(N-ethylmaleimide-sensitive factor) Now v-SNARE can betransported back to the donor compartment to be reusedSeveral SNARE complexes working at the secretoryendo-cytic pathway have been identified In mammalian cellstwo SNARE complexes have been implicated in intra-Golgitransport [160] A complex is formed of v-SNARE GS15 andthe t-SNAREs syntaxin5 GOS28 and Ykt6 is involved inCOPI-dependent intra-Golgi transport The second complexis formed of syntaxin 5 membrin (GS27) ERS24Sec22 andrBet1 the last one acting as v-SNARE This second complexhas been also involved in the fusion ER-derived elementswith the cis-Golgi and possible intra-Golgi transport Thedistribution of these SNAREs across the Golgi stack isdifferent Thus in general the components of the first com-plex increase in concentration toward the trans side whereasthe components of the second complex decrease [161]supporting the idea that these complexes mediate transportevents in opposite directions Syntaxin 5 which is present inboth complexes is distributed homogeneously through thestack SNARE complex assembly is regulated by SM (Sec1Munc18) proteins a family of cytosolic proteins Sly1 I isthe only member of this family operating at the ER-Golgiarea where it interacts with syntaxin 5 and syntaxin 18 at

the Golgi and ER respectively and controls anterograde andretrograde transport between these compartments [162]

Rab proteins are a family of small GTPases regulatingmembrane transport by recruiting effector proteins [159 163]They are localized at the cytoplasmic face of secretory andendocytic compartments and carriers and they have beenimplicated in vesicle budding uncoating mobility and trans-port Rab switches between an active form (GTP-bound) anda cytosolic inactive form (GDP-bound) Rab proteins in theGTP-bound form are reversibly associated with membranesby geranylgeranyl groups recruiting a variety of effectorsincluding sorting adaptors tethering factors kinases phos-phatases and motor proteins [163] The replacement of GDPby GTP is facilitated by guanine nucleotide exchange factors(GEFs) and their low intrinsic GTPase activity is enhancedby GTPase-activating proteins (GAP) Further regulation ofthe GTPGDP state and membrane association is providedby GDP dissociation inhibitor (GDI) and GDI displacementfactors (GDFs) Rab protein is a large family includingmore than 60 members in humans and 11 in yeast whichare specifically associated with distinct compartments andtransport events [163] Thus Rab proteins have also beenassociated with the control of membrane identity by control-ling local levels of phosphoinositides which concomitantlymay recruit specific proteins to certain compartments [164]The association of Rab proteins with specific membranes isguided by Rab escort protein (REP) which presents newlysynthesized Rab to geranylgeranyl transferase before target-ing the membranes The Golgi-associated Rab family playinga key role in Golgi maintenance and functioning includesRab1 Rab2 Rab6 Rab33B Rab18 and Rab43 [165] Rab1 andRab2 are involved in ER-to-Golgi transport Rab 1 is also veryimportant for Golgi ribbon maintenance Interestingly thelevels of expression or the distribution of this small GTPaseis affected in neurological disorders that show fragmentationof the Golgi ribbon [166] (Rendon et al [167]) Rab6 andmore specifically the Rab6AArsquo isoform is the most widelystudiedGolgi-associated Rab protein [168] It is important formaintaining Golgi structure and also for regulating transportin and out of the GC including a COPI-independent Golgi-to-ER transport [169] It is also associated with post-Golgicarriers where it recruits motor proteins [170 171] and alsoregulates the docking and fusion with the plasma membrane[172] At the Golgi stack it anchors the tethering factorsnecessary for attaching incoming vesicles The organizationof the Golgi ribbon the regulation of the number of cisternaein the stack and transport of coated vesicles is also associatedwith Rab6 and effectors [173] Rab33B is localized specificallyin the medial Golgi [174] where it is involved in Golgi-to-ER retrograde transport [175] Interestingly Rab6A recruitsspecific GEF that also interacts with Rab33B connecting theseRabs in a Rab cascade [176]Most probably Rab6 and Rab33Bwork together in the regulation of intra-Golgi and Golgi-to-ER transport [165] Less information is available about Rab43and Rab18 but they are also thought to be involved in ER-Golgi trafficking and Golgi organization

Tethering factors are a group of membrane-associatedproteins or multisubunit complexes that link transport vesi-cles with the targetmembranes to ensure correct docking and

ISRN Cell Biology 7

fusion They have recently been classified into three classesoligomeric complexes that work as Rab effectors and bindsSNARE oligomeric complexes that function as GEFs for Rabproteins and finally coiled-coil tethers [177] Proteins withextensive coiled-coil domains are long allowing long distancetethering These bridges not only facilitate the formation ofSNARE complexes but also may provide an initial specificityfor membrane fusionMembers of this family associated withthe Golgi are called golgins [178] In addition to tetheringthey have a role in Golgi stacking and form the Golgi matrixThis family includes p115 and GM130 the first of which isassociated with COPI and COPII vesicles the ERGIC andcis-Golgi membranes This protein is believed to be involvedin tethering of COPII vesicles to ERGIC membranes and thetransport events from these elements to the cis-Golgi It is alsopossible that it participates in transport between cisternaeThe recruitment of p115 to membranes is Rab1 dependentIt also interacts with ER-Golgi SNAREs COG subunits andother coiled-coil proteins such as GM130 and giantin Thesignificance of the last interaction is not clear GM130 isanother coiled-coil protein associated with the cis Golgi Itinteracts with many proteins including GRASP65 p115 Rab1Rab2 Rab33b and sintaxin5 P115 and GM130 are membersof the family of golgins which were first identified as Golgi-localized autoantigens using antibodies derived from thesera of patients with a variety of autoimmune disorders Asindicated above GM130 and p115 are also components ofthe Golgi matrix Apart from their role as tethers togetherwith other members of the golgin family such as GRASP65and giantin they are involved in maintaining the stackedmorphology of the cisterna and the Golgi ribbon [179]

Multisubunit complexes associated with the Golgiinclude Dsl1 COG and TRAPPIII [177] Dsl1 is a three-unitcomplex involved in Golgi-to-ER transport where it acts astethering COPI vesicles It interacts and stabilizes an SNAREcomplex at the ER The conserved oligomeric Golgi (COG)complex formed of 8 subunits (Cog1ndash8) found at the cis- andmedial Golgi cisternae is believed to be involved in transportto the Golgi and intra-Golgi recycling of Golgi resident pro-teins [180] Components of this tethering factor interactwith COPI components SNARE proteins (syntaxin 5) andcoiled-coil tether (p115) and are the effectors of several Rabproteins (Rab1 Rab6) Transport protein particle (TRAPP) isanother multisubunit complex that works as tethering factor[181] Two complexes have been identified TRAPP I andTRAPPII which are involved in entry and exit from theGC tethering COPII and COPI vesicles respectively Theywork as GEF for Rab1 and the activation of this GTPasemight recruit other tethers (as p115 or COG) [177] Howeverthey do not interact directly with SNAREs It is possible thatthere is a cascade of tethering factors that facilitates cargotransport

6 Intra-Golgi Transport

The mode of transport across the GC remains controversialTwo main models have been proposed vesicular transportand cisternal maturation The first one proposes that Golgi

cisternae are static so that the cargo must move via vesiclesThe second model support that cisterna are dynamic struc-tures that move from the cis to trans Golgi sideThus accord-ing to this model the entire cisterna is the carrier In thesemodels COPI-coated vesicles are responsible for antero-grade and retrograde transport respectively (Figure 3) Sinceneither of these models explains all the experimental data acombination of the same models and new models have beenproposed (see below)

61 Vesicular Transport Model This model was launchedby Palade in 1975 and was widely accepted for many yearsbecause it provides a good explanation for the well-knowncompartmentalization of the Golgi resident enzymes In thismodel it is assumed that cisternae are stable compartmentsso that the cargo must leave one cisterna and move to thenext in order to advance through the stack This process ismediated by vesicles The model was strongly supported bythe discovery of COPI and COPII vesicles [182] COPI wereidentified in in vitro assays as being responsible for antero-grade transport between cisterna [107] In these cell-freeexperiments when the formation of COPI was inhibitedanterograde was blocked [183 184] On the other hand itwas clearly demonstrated that COPII vesicles are involved inER exit and transport to the GC [87] Soon it was assumedthat COPII and COPI vesicles act sequentially in the earlysecretory pathway that is ER-to-Golgi and intra-Golgitransport respectively However new experimental data castdoubt on the model First of all a clear role of COPI vesiclesin retrograde transport was demonstrated [120 185] To fitthese data with the model it was postulated that there weretwo types of COPI vesicles involved in anterograde and retro-grade transport at the Golgi stack [186] ldquoPercolatingrdquo COPIvesiclesmaymove bidirectionally up and down in the stack ina random way but allowing a net rate of flow of anterogradecargo in the cis-to-trans direction [187] However immuno-cytochemical [188] and proteomic [9] analysis of thesevesicles showed that they are mostly devoid of anterogradetransport markers Thus the role of COPI vesicles remainscontroversial [189] The small number of Golgi-associatedSNARE and Rab proteins also argues against multiple fusionevents between vesicles and every cisterna in the stacks Oneproblem is that this model does not explain the transport oflarge cargo such as procollagen (300 nm rigid rod) [190] oralgal scales (up to 15ndash2 120583m) [191] within 50ndash60 nm vesiclesInterestingly scales which are electron dense and can beeasily visualized are not observed within vesicles The exis-tence of megavesicles transporting large (gt400 nm) proteinaggregates has been described in an artificial system [192]but it is not clear that this a general mechanism used bynonmodified cells [190]

62 Cisternal Maturation Model This model was postu-lated in the early epoque of electron microscopy [193] andupdated as cisternal progression-maturation model [190194] According to this model cisternae are formed at thecis side of the GC by fusion of ER-derived membranes andthen these newly formed membranes move from the cis to

8 ISRN Cell Biology

Tubules Retrograde COPI vesicles

Cisternal maturation

Anterograde COPI vesicles

Retrograde COPI vesicles

Vesicular transport

Tubules

(a)

(b)

(c)

(d)

Figure 3 Putative role of COPI-coated vesicles and tubules according to vesicular transport and cisternal maturation models for intra-Golgitransport According to vesicular transport model cisternae are static Anterograde transport may be mediated by COPI-coated vesicles andtubular cisternal connections Another type of COPI-coated vesicles mediates retrograde transport (ie the retrieval of proteins that haveescaped from the endoplasmic reticulum) According to cisternal maturation model cisternae move from cis (a) to trans Golgi sides (d)COPI-coated vesicles and transient tubules may be involved in the recycling of Golgi resident proteins (retrograde transport)

the trans side where they become post-Golgi carriers Thusnewly formed cisterna gradually displaces older cisternaetowards the trans side In this model it is not necessary forthe cargo to leave the cisterna and the whole cisterna is takento act as a carrier This model explains the transport of largecargo and an analysis of procollagen transport fits this modelvery well [190] These large molecules are detected in largedistensions at the lateral edge of the cisterna in their transitthrough the stack These distensions are always connected

to the cisterna so that procollagen is not transported bylarge vesicles In contrast the model does not explain thepolarity of the stack and what happens with resident enzymeswhen cisternae disappear at the trans side To overcomethese problems it was assumed that Golgi resident enzymesare packed into COPI vesicles during cisternal progressionand transported backwards Thus Golgi enzymes are notlost but recycled in a trans-to-cis direction maintainingthe polarity of this organelle [195] The cisternae mature by

ISRN Cell Biology 9

acquiring and then losing specific Golgi-resident proteinsThe presence of Golgi resident enzymes in COPI vesicles hasbeen demonstrated [188] although their relative concentra-tion is controversial Life cell imaging studies in yeast stronglysupport this model In Saccharomyces cerevisiae the Golgiis not stacked so that individual cisterna can be analyzedseparately Using cis and trans Golgi markers it was directlydemonstrated that cisternae mature (ie the apparentlyconversion of one type of cisterna into another) [196 197]The cisternal maturation model seems to be more efficientgiven that it would seem easier to transport anterograde cargousing a large carrier (the cisterna) than to use many smallvesicles between adjacent cisternae and repeating this processseveral times until reaching the TGN It is also intuitive thatperi-Golgi vesicles should be restricted to more selective andsmaller trafficking the retrograde pathway

63 Alternative Models Given that none of these modelscompletely explains all the experimental data new modelshave been postulated although some of them are variationsof the two main models

Dual transport model one possibility is that these twomodels are not mutually exclusive but rather complementaryand working simultaneously [198] Cisternae may moveslowly whereas vesicles transport anterograde and retrogradecargo more rapidly Large molecules may use the cisternalmaturation mechanism while small molecules can be trans-ported using vesicular transport [186 198]

Rapid partitioning model This model is based on therapid partitioning of transmembrane cargo and residentenzymes between two lipid phases According to this modelthe GC works as a single compartment but contains pro-cessing and export domains [199] When the cargo reachesthe Golgi it associates with these domains and then leavesthe compartment from every level Again this model hasdifficulty in explaining the polarity of the cisternae and doesnot help visualize the Golgi stack as a single compartment

Kiss-and-runmodelThis model is based onmechanismsoperating in other systems such as endosomes and lysosomesThismodel proposes that two cisternaemay fuse to each otherthrough narrow tubules connecting their lumens transientlyand allowing the transit of cargo before separating [200] Inthis model anterograde transport and retrograde transportoccur simultaneously and a specific retrograde pathway is notnecessary This model may explain several aspects of Golgitransport including the transport of large molecules How-ever some assumptions of the model need to be confirmed(ig machinery and mechanisms for the fusion and fission ofconnections) It is also not clear how all the experimental dataabout the role of COPI coats in retrograde transport fit thismodel

Intra-Golgi transportmediated by tubulesThe absence ofcargo in COPI vesicles suggests that other transport interme-diates such as tubules may operate at the GC As mentionedabove tubules are a common structure surrounding the stackTubules may be involved in the anterograde movement ofcargo through this organelleThe ER and all cisternae may bedirectly connected by tubules and cargo might move along

the secretory pathway like food through the gut [201] Infact conditions that stimulated protein secretion increasethe number of tubular connections between cisternae [136137] Conversely tubules may establish transient connectionsbetween compartments helping COPI vesicles to transportGolgi enzymes retrogradely as indicated by the cisternalmaturation model [46] (Figure 3) Cisternal maturation inyeast occurs although slowly without COPI vesicles suggest-ing that tubules may replace them [197] Low temperature-induced Golgi tubules are enriched in Golgi enzymes andSNARE and Rab proteins involved in intra-Golgi transportwhereas they exclude other proteins associated with ER-Golgi transport [139] Whether the tubules found in thismodel are representative of the carriers involved in intra-Golgi transport remains to be established

7 Concluding Remarks

A century after the discovery of the ldquoapparato reticolareinternordquo [202] it is clear that no model for intra-Golgi trans-port explains all the experimental data But it is also true thatthe ldquohigh polarityrdquo that exits the field has stimulated intenseresearch Recently developed high-resolution methodologiesmay give important clues in this respect Of special interestis the analysis of the structure and composition of tubularand vesicular carriers High-resolution immunocytochemi-cal techniques in combination with electron tomography aswell as proteomic analysis of highly purified samples maysolve the problem or at least definitively reject some modelsIn the end it is possible that each cell type depending of itsspecial characteristics uses a givenmechanism of intra-Golgitransport It also remains possible that a single cell usesdifferent mechanisms of intra-Golgi transport depending onthe amount and type of cargo or its physiological statusMeanwhile cisternal maturation in combination with tubulartransient connections is a very attractive and intuitive modelthat seems to fit most experimental data

Acknowledgments

The work in this paper was supported by Grants fromthe Ministerio de Ciencia e Innovacion (Spain) ConsoliderCOAT (CSD2009-00016) and Fundacion Seneca de la Comu-nidadAutonoma de la Region deMurcia (04542GERM06)

References

[1] G Palade ldquoIntracellular aspects of the process of protein syn-thesisrdquo Science vol 189 no 4200 pp 347ndash358 1975

[2] W Nickel and C Rabouille ldquoMechanisms of regulated uncon-ventional protein secretionrdquo Nature Reviews Molecular CellBiology vol 10 no 2 pp 148ndash155 2009

[3] M G Farquhar and G E Palade ldquoThe Golgi apparatus (com-plex) (1954ndash1981) from artifact to center stagerdquo Journal of CellBiology vol 91 no 3 pp 77sndash103s 1981

[4] M G Farquhar and G E Palade ldquoThe Golgi apparatus 100years of progress and controversyrdquo Trends in Cell Biology vol8 no 1 pp 2ndash10 1998

10 ISRN Cell Biology

[5] C Wilson R Venditti L R Rega A Colanzi G DrsquoAngeloandM A De ldquoThe Golgi apparatus an organelle with multiplecomplex functionsrdquo Biochemical Journal vol 433 no 1 pp 1ndash92011

[6] J Lippincott-Schwartz E Snapp and A Kemvorthy ldquoStudyingprotein dynamics in living cellsrdquoNature Reviews Molecular CellBiology vol 2 no 6 pp 444ndash456 2001

[7] G Perinetti T Muller A Spaar R Polishchuk A Luini andA Egner ldquoCorrelation of 4Pi and electron microscopy to studytransport through single golgi stacks in living cells with superresolutionrdquo Traffic vol 10 no 4 pp 379ndash391 2009

[8] J Lippincott-Schwartz ldquoEmerging in vivo analyses of cellfunction using fluorescence imagingrdquo Annual Review of Bio-chemistry vol 80 pp 327ndash332 2011

[9] A Gilchrist C E Au J Hiding et al ldquoQuantitative proteomicsanalysis of the secretory pathwayrdquo Cell vol 127 no 6 pp 1265ndash1281 2006

[10] J Gannon J J Bergeron and T Nilsson ldquoGolgi and relatedvesicle proteomics simplify to identifyrdquo Cold Spring HarborPerspectives in Biology vol 3 no 12 2011

[11] F Bard L Casano A Mallabiabarrena et al ldquoFunctionalgenomics reveals genes involved in protein secretion and Golgiorganizationrdquo Nature vol 439 pp 604ndash607 2006

[12] J W Slot and H J Geuze ldquoImmunoelectron microscopicexploration of theGolgi complexrdquo Journal ofHistochemistry andCytochemistry vol 31 no 8 pp 1049ndash1056 1983

[13] D ZeuschnerW J C Geerts E vanDonselaar et al ldquoImmuno-electron tomography of ER exit sites reveals the existence of freeCOPII-coated transport carriersrdquoNature Cell Biology vol 8 no4 pp 377ndash383 2006

[14] R S Polishchuk E V Polishchuk P Marra et al ldquoCorrelativelight-electron microscopy reveals the tubular-saccular ultra-structure of carriers operating between Golgi apparatus andplasma membranerdquo Journal of Cell Biology vol 148 no 1 pp45ndash58 2000

[15] B S Donohoe S Mogelsvang and L A Staehelin ldquoElectrontomography of ER Golgi and related membrane systemsrdquoMethods vol 39 no 2 pp 154ndash162 2006

[16] N K Gonatas A Stieber and J O Gonatas ldquoFragmentationof the Golgi apparatus in neurodegenerative diseases and celldeathrdquo Journal of the Neurological Sciences vol 246 no 1-2 pp21ndash30 2006

[17] M C Derby and P A Gleeson ldquoNew insights into membranetrafficking and protein sortingrdquo International Review of Cytol-ogy vol 261 pp 47ndash116 2007

[18] A A Mironov and M Pavelka The Golgi Apparatus State ofthe Art 110 Years after Camillo Golgirsquos Discovery Springer WienNewYork NY USA 2008

[19] E Papanikou and B S Glick ldquoThe yeast Golgi apparatusinsights and mysteriesrdquo FEBS Letters vol 583 no 23 pp 3746ndash3751 2009

[20] J H Wei and J Seemann ldquoMitotic division of the mammalianGolgi apparatusrdquo Seminars in Cell and Developmental Biologyvol 20 no 7 pp 810ndash816 2009

[21] M Anitei and B Hoflack ldquoExit from the trans-Golgi networkfrom molecules to mechanismsrdquo Current Opinion in Cell Biol-ogy vol 23 no 4 pp 443ndash451 2011

[22] J Klumperman ldquoArchitecture of the mammalian Golgirdquo ColdSpring Harbor Perspectives in Biology vol 3 no 7 Article IDa005181 2011

[23] YWang and J Seemann ldquoGolgi biogenesisrdquoCold Spring HarborPerspectives in Biology vol 3 no 10 Article ID a005330 2011

[24] K W Moremen M Tiemeyer and A V Nairn ldquoVertebrateprotein glycosylation diversity synthesis and functionrdquoNatureReviews Molecular Cell Biology vol 13 pp 448ndash462 2012

[25] A J Dalton and M D Felix ldquoA comparative study of the Golgicomplexrdquo The Journal of Biophysical and Biochemical Cytologyvol 2 no 4 pp 79ndash84 1956

[26] A Rambourg Y Clermont and A Marraud ldquoThree dimen-sional structure of the osmium impregnated Golgi apparatus asseen in the high voltage electronmicroscoperdquoAmerican Journalof Anatomy vol 140 no 1 pp 27ndash46 1974

[27] A Rambourg Y Clermont and L Hermo ldquoThree-dimensionalarchitecture of the Golgi apparatus in Sertoli cells of the ratrdquoAmerican Journal of Anatomy vol 154 no 4 pp 455ndash476 1979

[28] M S Ladinsky D NMastronarde J RMcIntosh K E Howelland L A Staehelin ldquoGolgi structure in three dimensionsfunctional insights from the normal rat kidney cellrdquo Journal ofCell Biology vol 144 no 6 pp 1135ndash1149 1999

[29] R S Taylor S M Jones R H Dahl M H Nordeen andK E Howell ldquoCharacterization of the Golgi complex clearedof proteins in transit and examination of calcium uptakeactivitiesrdquo Molecular Biology of the Cell vol 8 no 10 pp 1911ndash1931 1997

[30] MMWuM Grabe S Adams R Y Tsien H P HMoore andT E Machen ldquoMechanisms of pH regulation in the regulatedsecretory pathwayrdquo Journal of Biological Chemistry vol 276 no35 pp 33027ndash33035 2001

[31] J HWei and J Seemann ldquoUnraveling theGolgi ribbonrdquoTrafficvol 11 no 11 pp 1391ndash1400 2010

[32] A A Mironov and G V Beznoussenko ldquoMolecular mecha-nisms responsible for formation of Golgi ribbonrdquoHistology andHistopathology vol 26 no 1 pp 117ndash133 2011

[33] B Storrie JWhite S Rottger E H K Stelzer T Suganuma andT Nilsson ldquoRecycling of Golgi-resident glycosyltransferasesthrough the ER reveals a novel pathway and provides anexplanation for nocodazole-induced Golgi scatteringrdquo Journalof Cell Biology vol 143 no 6 pp 1505ndash1521 1998

[34] J Fan Z Hu L Zeng et al ldquoGolgi apparatus and neurode-generative diseasesrdquo International Journal of DevelopmentalNeuroscience vol 26 no 6 pp 523ndash534 2008

[35] Y Fujita EOhamaMTakatama S Al-Sarraj andKOkamotoldquoFragmentation of Golgi apparatus of nigral neurons with120572-synuclein-positive inclusions in patients with Parkinsonrsquosdiseaserdquo Acta Neuropathologica vol 112 no 3 pp 261ndash2652006

[36] G Thorne-Tjomsland M Dumontier and J C Jamiesonldquo3D topography of noncompact zone Golgi tubules in ratspermatids a computer-assisted serial section reconstructionstudyrdquoThe Anatomical Record vol 250 pp 381ndash396 1998

[37] A S Opat C Van Vliet and P A Gleeson ldquoTrafficking andlocalisation of residentGolgi glycosylation enzymesrdquoBiochimievol 83 no 8 pp 763ndash773 2001

[38] M G Farquhar and H P Hauri ldquoProtein sorting and vesiculartraffic in the Golgi apparatusrdquo inTheGolgi Apparatus E Bergerand J Roth Eds pp 63ndash128 Birkhauser Basel Switzerland1997

[39] G van Meer ldquoLipids of the Golgi membranerdquo Trends in CellBiology vol 8 no 1 pp 29ndash33 1998

[40] J C M Holthuis T Pomorski R J Raggers H Sprong andG Van Meer ldquoThe organizing potential of sphingolipids in

ISRN Cell Biology 11

intracellular membrane transportrdquo Physiological Reviews vol81 no 4 pp 1689ndash1723 2001

[41] D K Banfield ldquoMechanisms of protein retention in the GolgirdquoCold Spring Harbor Perspectives in Biology vol 3 Article IDa005264 2011

[42] D J Gill J Chia J Senewiratne and F Bard ldquoRegulation ofO-glycosylation through Golgi-to-ER relocation of initiationenzymesrdquo Journal of Cell Biology vol 189 no 5 pp 843ndash8582010

[43] A Sesso F Paulo de Faria E S M Iwamura and H Correa ldquoAthree-dimensional reconstruction study of the rough ER-Golgiinterface in serial thin sections of the pancreatic acinar cell ofthe ratrdquo Journal of Cell Science vol 107 no 3 pp 517ndash528 1994

[44] Y Clermont A Rambourg and L Hermo ldquoConnectionsbetween the various elements of the cis- and mid-compart-ments of the Golgi apparatus of early rat spermatidsrdquo Anatomi-cal Record vol 240 no 4 pp 469ndash480 1994

[45] A Rambourg and Y Clermont ldquoThree-dimensional structureof the Golgi apparatus in mammalian cellsrdquo in The GolgiApparatus E G Berger and J Roth Eds pp 37ndash61 BirkhauserBasel Switzerland 1997

[46] G Vivero-Salmeron J Ballesta and J A Martınez-MenarguezldquoHeterotypic tubular connections at the endoplasmic reticu-lum-Golgi complex interfacerdquo Histochemistry and Cell Biologyvol 130 pp 709ndash717 2008

[47] C vanVliet E CThomas AMerino-Trigo R D Teasdale andP A Gleeson ldquoIntracellular sorting and transport of proteinsrdquoProgress in Biophysics and Molecular Biology vol 83 no 1 pp1ndash45 2003

[48] G Griffiths S Pfeiffer K Simons and K Matlin ldquoExit of newlysynthesized membrane proteins from the trans cisterna of theGolgi complex to the plasmamembranerdquo Journal of Cell Biologyvol 101 no 3 pp 949ndash964 1985

[49] G Griffiths S D Fuller R BackMHollinshead S Pfeiffer andK Simons ldquoThe dynamic nature of the Golgi complexrdquo Journalof Cell Biology vol 108 no 2 pp 277ndash297 1989

[50] H J Geuze and D J Morre ldquoTrans-Golgi reticulumrdquo Journal ofElectron Microscopy Technique vol 17 no 1 pp 24ndash34 1991

[51] Y Clermont A Rambourg and L Hermo ldquoTrans-Golgi net-work (TGN) of different cell types three-dimensional structuralcharacteristics and variabilityrdquo Anatomical Record vol 242 no3 pp 289ndash301 1995

[52] R S Polishchuk andA AMironov ldquoStructural aspects of Golgifunctionrdquo Cellular andMolecular Life Sciences vol 61 no 2 pp146ndash158 2004

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[54] F Bard and V Malhotra ldquoThe formation of TGN-to-plasma-membrane transport carriersrdquo Annual Review of Cell andDevelopmental Biology vol 22 pp 439ndash455 2006

[55] R D Klausner J G Donaldson and J Lippincott-SchwartzldquoBrefeldin A insights into the control of membrane traffic andorganelle structurerdquo Journal of Cell Biology vol 116 no 5 pp1071ndash1080 1992

[56] J Llopis J M McCaffery A Miyawaki M G Farquhar andR Y Tsien ldquoMeasurement of cytosolic mitochondrial andGolgi pH in single living cells with green fluorescent proteinsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 12 pp 6803ndash6808 1998

[57] H HMollenhauer andD J Morre ldquoThe tubular network of theGolgi apparatusrdquo Histochemistry and Cell Biology vol 109 no5-6 pp 533ndash543 1998

[58] L Orci A Perrelet and J E Rothman ldquoVesicles on stringsMorphological evidence for processive transport within theGolgi stackrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 95 no 5 pp 2279ndash2283 1998

[59] Y Xiang and Y Wang ldquoNew components of the Golgi matrixrdquoCell and Tissue Research vol 344 no 3 pp 365ndash379 2011

[60] N Nakamura C Rabouille R Watson et al ldquoCharacterizationof a cis-Golgi matrix protein GM130rdquo Journal of Cell Biologyvol 131 no 6 pp 1715ndash1726 1995

[61] P Slusarewicz T Nilsson N Hui R Watson and G WarrenldquoIsolation of amatrix that bindsmedial Golgi enzymesrdquo Journalof Cell Biology vol 124 no 4 pp 405ndash413 1994

[62] G Egea and R M Rios ldquoThe role of the cytoskeleton in thestructure and function of the Golgi apparatusrdquo in The GolgiApparatus A A Mironov and M Pavelka Eds pp 270ndash300Springer NewYork NY USA 2008

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[64] R M Rios and M Bornens ldquoThe Golgi apparatus at the cellcentrerdquoCurrent Opinion in Cell Biology vol 15 pp 60ndash66 2003

[65] S Yadav and A D Linstedt ldquoGolgi positioningrdquo Cold SpringHarbor Perspectives in Biology vol 3 pp 1ndash17 2011

[66] J K Burkhardt ldquoThe role of microtubule-based motor proteinsin maintaining the structure and function of the Golgi com-plexrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp 113ndash126 1998

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[68] S Rivero J Cardenas M Bornens and R M Rios ldquoMicro-tubule nucleation at the cis-side of the golgi apparatus requiresAKAP450 and GM130rdquo The EMBO Journal vol 28 no 8 pp1016ndash1028 2009

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12 ISRN Cell Biology

[75] A Disanza and G Scita ldquoCytoskeletal regulation coordinatingactin and microtubule dynamics in membrane traffickingrdquoCurrent Biology vol 18 no 18 pp R873ndashR875 2008

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[78] T F Roth and K R Porter ldquoYolk protein uptake in the oocyteof the mosquito Aedes aegypti Lrdquo The Journal of Cell Biologyvol 20 pp 313ndash332 1964

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[81] B M F Pearse and M S Robinson ldquoClathrin adaptors andsortingrdquo Annual Review of Cell Biology vol 6 pp 151ndash171 1990

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[83] T Kirchhausen ldquoClathrinrdquo Annual Review of Biochemistry vol69 pp 699ndash727 2000

[84] E Rodriguez-Boulan and A Musch ldquoProtein sorting in theGolgi complex shifting paradigmsrdquo Biochimica et BiophysicaActa vol 1744 no 3 pp 455ndash464 2005

[85] M A McNiven H Cao K R Pitts and Y Yoon ldquoThe dynaminfamily of mechanoenzymes pinching in new placesrdquo Trends inBiochemical Sciences vol 25 no 3 pp 115ndash120 2000

[86] E Eisenberg and L E Greene ldquoMultiple roles of auxilin andHsc70 in clathrin-mediated endocytosisrdquo Traffic vol 8 no 6pp 640ndash646 2007

[87] C Barlowe L Orci T Yeung et al ldquoCOPII a membrane coatformed by sec proteins that drive vesicle budding from theendoplasmic reticulumrdquo Cell vol 77 no 6 pp 895ndash907 1994

[88] L C Bickford E Mossessova and J Goldberg ldquoA structuralview of the COPII vesicle coatrdquo Current Opinion in StructuralBiology vol 14 no 2 pp 147ndash153 2004

[89] D Jensen and R Schekman ldquoCOPII-mediated vesicle forma-tion at a glancerdquo Journal of Cell Science vol 124 no 1 pp 1ndash42011

[90] T Kirchhausen ldquoMaking COPII coatsrdquo Cell vol 129 no 7 pp1251ndash1252 2007

[91] C Barlowe ldquoCOPII and selective export from the endoplasmicreticulumrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp67ndash76 1998

[92] J A Martınez-Menarguez H J Geuze J W Slot and JKlumperman ldquoVesicular tubular clusters between the ER andGolgi mediate concentration of soluble secretory proteins byexclusion fromCOPI-coated vesiclesrdquoCell vol 98 no 1 pp 81ndash90 1999

[93] K Saito M Chen F Bard et al ldquoTANGO1 facilitates cargoloading at endoplasmic reticulum exit sitesrdquo Cell vol 136 no5 pp 891ndash902 2009

[94] L Jin K B Pahuja K E Wickliffe et al ldquoUbiquitin-dependentregulation of COPII coat size and functionrdquo Nature vol 482pp 495ndash500 2012

[95] H P Hauri and A Schweizer ldquoThe endoplasmic reticulum-Golgi intermediate compartmentrdquo Current Opinion in CellBiology vol 4 no 4 pp 600ndash608 1992

[96] S I Bannykh T Rowe and W E Balch ldquoThe organizationof endoplasmic reticulum export complexesrdquo Journal of CellBiology vol 135 no 1 pp 19ndash35 1996

[97] J Saraste and E Kuismanen ldquoPre- and post-Golgi vacuolesoperate in the transport of Semliki Forest virus membraneglycoproteins to the cell surfacerdquo Cell vol 38 no 2 pp 535ndash549 1984

[98] A Schweizer J A M Fransen K Matter T E Kreis L GinselandH PHauri ldquoIdentification of an intermediate compartmentinvolved in protein transport from endoplasmic reticulum toGolgi apparatusrdquo European Journal of Cell Biology vol 53 no 2pp 185ndash196 1990

[99] H Ben-Takaya K Miura R Pepperkok and H P Hauri ldquoLiveimaging of bidirectional traffic from the ERGICrdquo Journal of CellScience vol 118 no 2 pp 357ndash367 2005

[100] Y C Zhang Y Zhou C Z Yang and D S Xiong ldquoA reviewof ERGIC-53 its structure functions regulation and relationswith diseasesrdquo Histology and Histopathology vol 24 no 9 pp1193ndash1204 2009

[101] J F Presley N B Cole T A Schroer K Hirschberg K JM Zaal and J Lippincott-Schwartz ldquoER-to-Golgi transportvisualized in living cellsrdquo Nature vol 389 no 6646 pp 81ndash851997

[102] J A Martınez-Menarguez H J Geuze and J Ballesta ldquoIdenti-fication of two types of beta-COP vesicles in the Golgi complexof rat spermatidsrdquo European Journal of Cell Biology vol 71 pp137ndash143 1996

[103] J Lippincott-Schwartz J G Donaldson A Schweizer et alldquoMicrotubule-dependent retrograde transport of proteins intothe ER in the presence of brefeldin A suggests an ER recyclingpathwayrdquo Cell vol 60 no 5 pp 821ndash836 1990

[104] A Girod B Storrie J C Simpson et al ldquoEvidence for a COP-I-independent transport route from the Golgi complex to theendoplasmic reticulumrdquo Nature Cell Biology vol 1 no 7 pp423ndash430 1999

[105] V Popoff F Adolf B Brugger and F Wieland ldquoCOPI buddingwithin the Golgi stackrdquo Cold Spring Harbor Perspectives inBiology vol 3 Article ID a005231 2011

[106] J Moelleken J Malsam M J Betts et al ldquoDifferential localiza-tion of coatomer complex isoforms within the Golgi apparatusrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 104 no 11 pp 4425ndash4430 2007

[107] L Orci B S Glick and J E Rothman ldquoA new type of coatedvesicular carrier that appears not to contain clathrin its possiblerole in protein transport within theGolgi stackrdquoCell vol 46 no2 pp 171ndash184 1986

[108] V Malhotra T Serafini L Orci J C Shepherd and J ERothman ldquoPurification of a novel class of coated vesiclesmediating biosynthetic protein transport through the Golgistackrdquo Cell vol 58 no 2 pp 329ndash336 1989

[109] M G Waters T Serafini and J E Rothman ldquolsquoCoatomerrsquo acytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesiclesrdquo Nature vol 349 no 6306 pp248ndash251 1991

[110] T Serafini L Orci M Amherdt M Brunner R A Kahn andJ E Rothman ldquoADP-ribosylation factor is a subunit of the coatof Golgi-derived COP-coated vesicles a novel role for a GTP-binding proteinrdquo Cell vol 67 no 2 pp 239ndash253 1991

ISRN Cell Biology 13

[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

[112] K Kawamoto Y Yoshida H Tamaki et al ldquoGBF1 a guaninenucleotide exchange factor for ADP-ribosylation factors islocalized to the cis-Golgi and involved inmembrane associationof the COPI coatrdquo Traffic vol 3 no 7 pp 483ndash495 2002

[113] R Garcıa-Mata T Szul C Alvarez and E Sztul ldquoADP-ribosylation factorCOPI-dependent events at the endoplas-mic reticulum-Golgi interface are regulated by the guaninenucleotide exchange factor GBF1rdquoMolecular Biology of the Cellvol 14 no 6 pp 2250ndash2261 2003

[114] H Inoue and P A Randazzo ldquoArf GAPs and their interactingproteinsrdquo Traffic vol 8 no 11 pp 1465ndash1475 2007

[115] G Tanigawa L Orci M Amherdt M Ravazzola J B Helmsand J E Rothman ldquoHydrolysis of bound GTP by ARF proteintriggers uncoating of Golgi- derived COP-coated vesiclesrdquoJournal of Cell Biology vol 123 no 6 pp 1365ndash1371 1993

[116] Y Shiba and P A Randazzo ldquoArfGAP1 function in COPImediated membrane traffic currently debated models andcomparison to other coat-binding ArfGAPsrdquo Histology andHistopathology vol 27 pp 1143ndash1153 2012

[117] J Bigay P Gounon S Roblneau and B Antonny ldquoLipidpacking sensed by ArfGAP1 couples COPI coat disassembly tomembrane bilayer curvaturerdquo Nature vol 426 no 6966 pp563ndash566 2003

[118] W Nickel J Malsam K Gorgas et al ldquoUptake by COPI-coatedvesicles of both anterograde and retrograde cargo is inhibitedby GTP120574S in vitrordquo Journal of Cell Science vol 111 no 20 pp3081ndash3090 1998

[119] R Beck M Rawet F T Wieland and D Cassel ldquoThe COPIsystemmolecularmechanisms and functionrdquo FEBS Letters vol583 pp 2701ndash2709 2009

[120] F Letourneur E C Gaynor S Hennecke et al ldquoCoatomeris essential for retrieval of dilysine-tagged proteins to theendoplasmic reticulumrdquo Cell vol 79 no 7 pp 1199ndash1207 1994

[121] R Schindler C Itin M Zerial F Lottspeich and H P HaurildquoERGIC-53 a membrane protein of the ER-Golgi intermediatecompartment carries an ER retention motifrdquo European Journalof Cell Biology vol 61 no 1 pp 1ndash9 1993

[122] L P Jackson M Lewis H M Kent et al ldquoMolecular basis forrecognition of dilysine trafficking motifs by COPIrdquo Develop-mental Cell vol 23 pp 1ndash8 2012

[123] W Nickel K Sohn C Bunning and F T Wieland ldquop23 Amajor COPI-vesicle membrane protein constitutively cyclesthrough the early secretory pathwayrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 94 no21 pp 11393ndash11398 1997

[124] J C Semenza K G Hardwick N Dean and H R BPelham ldquoERD2 a yeast gene required for the receptor-mediatedretrieval of luminal ER proteins from the secretory pathwayrdquoCell vol 61 no 7 pp 1349ndash1357 1990

[125] I Majoul M Straub S W Hell R Duden and H D SolingldquoKDEL-cargo regulates interactions between proteins involvedin COPI vesicle traffic measurements in living cells usingFRETrdquo Developmental Cell vol 1 no 1 pp 139ndash153 2001

[126] B S Glick ldquoOrganization of the Golgi apparatusrdquo CurrentOpinion in Cell Biology vol 12 no 4 pp 450ndash456 2000

[127] R Blum D J Stephens and I Schulz ldquoLumenal targeted GFPused as a marker of soluble cargo visualises rapid ERGIC toGolgi traffic by a tubulo-vesicular networkrdquo Journal of CellScience vol 113 no 18 pp 3151ndash3159 2000

[128] J C Simpson T Nilsson and R Pepperkok ldquoBiogenesis oftubular ER-to-golgi transport intermediatesrdquoMolecular Biologyof the Cell vol 17 no 2 pp 723ndash737 2006

[129] K Hirschberg C M Miller J Ellenberg et al ldquoKinetic analysisof secretory protein traffic and characterization of Golgi toplasma membrane transport intermediates in living cellsrdquoJournal of Cell Biology vol 143 no 6 pp 1485ndash1503 1998

[130] D Toomre P Keller JWhite J C Olivo and K Simons ldquoDual-color visualization of trans-Golgi network to plasmamembranetraffic alongmicrotubules in living cellsrdquo Journal of Cell Sciencevol 112 no 1 pp 21ndash33 1999

[131] L Hermo A Rambourg and Y Clermont ldquoThree-dimensionalarchitecture of the cortical region of the Golgi apparatus in ratspermatidsrdquo American Journal of Anatomy vol 157 no 4 pp357ndash373 1980

[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

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Molecular Biology International

GenomicsInternational Journal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

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BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

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Nucleic AcidsJournal of

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Stem CellsInternational

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Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

2 ISRN Cell Biology

1

2

3

4

5

6

Figure 1 Cryosection of the Golgi complex of rat exocrine pan-creatic cells Typical image of a cross-sectioned Golgi complex 1 =endoplasmic reticulum exit site 2 = tubulovesicular elements associ-ated to ERGIC 3 = tubularmembranes associatedwith theCGN 4 =stack of cisternae 5 = TGN elements 6 = secretory granule Bar =200 nm

(Figures 1 and 2) The stack of cisternae is considered thecentral domain of the GC Cisternae are very narrow in thecenter and dilated at the lateral rims where they show coatedbuds The low areavolume ratio favors interaction betweenthe enzymatic machinery of membranes and the cargo Theyoften show fenestrations sometime appearing as large holesthat formwells [28]Themorphology of the stacked cisternaedepends on the cargo Thus when protein synthesis isblocked the cisternae are very thin and stacks show an onion-like organization [29]The pH is also important and a low pHinduces thin cisternae [30] In most mammalian cells Golgistacks are laterally connected to form continuous ribbonThe reason for this not known but could be related withadvanced functions such as polarized secretion cell motil-ity and signalling [31 32] The maintenance of the Golgiribbon depends on the microtubular cytoskeleton and abalanced inward and outward transport Microtubule de-polymerization induced bynocodazole breaks the ribbon intoministacks [33] a process that is reversible demonstratingthat the GC is a high dynamic organelle Interestingly theGolgi ribbon appeared fragmented into ministacks in manyneurological diseases including Parkinsonrsquos disease [16 3435] The lateral area of the stacks where one connects withanother is known as the noncompact region This shows acomplex morphology and is filled with vesicles and otherheterogeneous elements [36]

The composition of the cisternae is not homogeneous andit contains different sets of resident proteins Based on thisGolgi stacks have been classically divided into cismedial andtrans sides Cis cisternae receive newly synthesized proteinsand lipids from the ER while cargo exits the organelle atthe trans side taking 10ndash20 minutes to traverse the stack ERelements tightly associated with the transmost cisternaehave been described the role of which is not known butmay be related with the direct transfer of lipids between

lowast

lowastlowast

lowast

lowast

lowast

Figure 2 Cryosection of the Golgi complex of a rat exocrinepancreatic cell Face view of a single cisterna (G) showing the hugecomplexity of the surrounding tubulovesicular elements (asterisk)Without a detailed immunocytochemical analysis of their composi-tion and high-resolution structural study it is not possible to discernwhether these membranes represent the ERGIC CGN peri-Golgivesicles or tubules connecting the stacks laterally N=nucleus Bar =200 nm

these organelles [28] The primary role of the stack is theglycosylation of proteins and lipids In the GC there areglycosidases nucleotides sugar transporters and at least 200different glycosyltransferases [37] few of which are homo-geneously distributed through the Golgi stack For exam-ple enzymes associated with early and late steps of gly-cosylation are predominantly found at the cis and transsides respectively Peptide-GalNAc-transferase and GlcNAc-phosphotransferase are associated with the cis Golgi man-nosidase I and II GlcNAc transferase I and phosphodi-esterase to the medial Golgi and 120573-14-galactosyltransferaseand 120572-26-sialyltransferase to the trans side [38] Most pro-teins associated with the Golgi function (matrix proteinsRabs SNARE etc) also show a polarized distributionThere isalso a cis-trans gradient of cholesterol and sphingolipids [3940] The retention of transmembrane proteins within Golgimembranes depends on protein-protein interactions thecomposition and length of the transmembrane domain andcytoplasmic tail the lipid environment and their bind-ing affinity to coat complexes whereas the localization ofperipheral membrane proteins depends on protein-proteininteraction and the posttranslational addition of lipids [41]It should be noted that such polarization is not strict butrather proteins show a gradient-like distribution suggestinga dynamic equilibrium Supporting this concept the locationof N-acetylgalactosaminyl transferase the enzyme that initi-ates O-glycosylation is regulated by growth factors that caninduce its redistribution to the ER [42]

Associated to the cis Golgi side of the Golgi stack thereis a tubulovesicular system known as the cis-Golgi network(CGN)This is formed of tubules connected to the first Golgicisterna [43ndash46] a cisterna containing many fenestrations[28] In early electron microscopical studies these tubuleswere selectively stained with reducing osmic for prolongedtimes The boundaries and the functional relationship of this

ISRN Cell Biology 3

tubular network connected to the stack and ER-derived pre-Golgi tubule-vesicular elements (see below) remain to beestablished

The trans-Golgi network (TGN) is located at the transside and is the place where proteins are sorted packed anddelivered to their final destination (endolysosomal systemapical or basolateral membranes secretion) It is also thecompartment where secretory and endocytic routes converge[47] In the TGN the final steps of glycosylation (includingsulfation and sialylation) serine-linked O-phosphorylationand the proteolytic processing of hormone precursors takeplace The organization of these membranes depends on celltype Usually the TGN is formed by a network of tubulo-vesicular membranes connected to one or two transmostcisternae while secretory cells containing immature secre-tory granules However the TGN may be an independentcompartment adjacent to the stack or conversely at somedistance from the same [48ndash51] The tubular component isextensive in cells with a well-developed lysosomal system andreduced in secretory cells The structural variability of theTGN may be due to its capacity to secrete different types ofcargo [52] and it is not clear whether this compartment isdivided into subdomains representing specialized exit sitesfor different destinations [22 53 54] Although function-ally and structurally connected the TGN and Golgi stackare different compartments as demonstrated in the use ofbrefeldin A This fungal drug induces the tubulation of bothcompartments but fusion with the endosomal system or ERrespectively [55] The pH of the TGN is more acidic than themedialtrans cisternae (658 and 591 resp) [56]

The structure of the GC is supported by the so-calledGolgi matrix a ribosome-free area surrounding the cisternaeand formedby structural proteinsThismatrix is visualized byelectron microscopy as small fibers connecting the cisternae[57] and also connecting the Golgi membranes and transportvesicles [58] A large number of Golgi matrix componentshave been identified including Golgi reassembly stackingproteins (GRASPs) and golgins [59] with GM130 being thefirst component identified [60] Some of the componentswere identified as autoantigens and others were isolated fromdetergent-insoluble salt-resistant Golgi fractions [61] Thesecomponents are very dynamic and cycle betweenmembrane-associated and a cytoplasmic forms process that dependson posttranslational modifications such as phosphorylationMatrix proteins are involved in the regulation of membranetraffic and the maintenance of the Golgi structure Morerecently the matrix has been related to microtubule organi-zation signaling and regulation of apoptosis and cell cycle[59]

The organization of the Golgi ribbon also depends onthe microtubule and actin cytoskeleton [62 63] In non-polarized cells stacks are distributed around the microtubuleorganization center (MTOC) usually close to the nucleus[64 65] However microtubules are not essential for otherfunctions such as glycosylation or global secretion Thefinal position of the ribbon and transport into or from thisorganelle is determined by the action of molecular motorsThemovement of transport carriers from the periphery to theGC at the cell centre is mediated by the minus-end-directed

motor dynein This motor and its cofactor dynactin areessential for maintenance of the perinuclear position of theGolgi ribbon [66] The movement in the opposite directionis mediated by the plus-ended-directed motor kinesin Inter-estingly the GC is able to nucleate and stabilize microtubulesacting as a secondary MTOC [67] The cis-Golgi proteinGMAP210 recruits 120574-tubulin to this organelle AKAP450 a 120574-tubulin-interaction centrosomal protein is also found at theGolgi after recruitment by GM130 [68] At the trans-Golgithe nucleation of microtubules depends on microtubule-binding proteins CLASPs which are recruited to the Golgimembranes through the golgin GCC185 [69] This processis necessary for polarized secretion and the maintenanceof the Golgi ribbon [70] On the other hand actin hasbeen associated with coated transport vesicles and buds [71]Golgi membranes also contain molecules such as Arp23N-WASP or cdc42 that trigger actin polymerization [72]Actin filaments and actin-associated proteins are involved inpost-Golgi [73] andGolgi-to-ER [74] transport Interestinglythe action of the microtubule and actin cytoskeletons iscoordinated [75] One of the factors involved in this link is theprotein WHAMM (WASP homology associated with actinmembrane and microtubules) which is present in the Golgiand pre-Golgi elements This protein has domains that bindactin-binding proteins such as profilin andArp23 a domainthat directly bind microtubules and a domain required tobind lipids [76] WHAMM regulates carrier morphologyduring intracellular transport [77]

3 Transport Carriers Vesicles

The stacks are surrounded by small vesicles of different sizesand many of them are coated For example in two adjacentstacks of NRK cells of the sim400 vesicles found one halfwere coated [28]Three different types of coat complexes havebeen identified and characterized in detail (COPI COPIIclathrin) although the existence of other coat complexescannot be rejected

Clathrin-coated vesicles were the first to be identified [7879] Both their size (100 nm) and the coat thickness (18 nm)are larger than in COP vesicles [80] Clathrin is mainlyinvolved in transport fromGCor from the plasmamembraneto the endolysosomal system [81] In the Golgi area clathrin-coated vesicles and buds are associated with the trans-mostGolgi cisterna and TGN [28] where it is involved in theexport of mannose-6-phosphate receptors carrying newlysynthesized lysosomal enzymes [82] Clathrin is a proteincomplex formed by three heavy and three light chains thatassemble to make a basket-like structure made up of pen-tagons and hexagons [83]Their association with membranesand the recruitment of cargo is mediated by adaptor com-plexes Clathrin binds a variety of adaptor complexes involvedin different transport events In humans four ubiquitouslyexpressed adaptor complexes (AP1-4) and three Golgi-localized 120574-ear-containing ARF-binding proteins (GGA1-3)have been identified AP2 is restricted to the plasma mem-brane where it is involved in endocytosis whereas GGAsand AP1-4 are located at the TGN andor in endosomes [17]At theTGNAP1 andCGAproteins recognize specific signals

4 ISRN Cell Biology

present in mannose-6-phosphate receptors and contribute tothe sorting of these receptors which their cargo hydrolysesinto clathrin-coated vesicles [82] AP1 AP3 and AP4 (in thiscase independently of clathrin) are involved in the sortingof lysosomal membrane proteins at the TGN In polarizedcells AP1 AP3 and AP4 are involved in the sorting of baso-lateral membrane proteins but probably through a clathrin-independent mechanism [84] The binding of cargo andadaptor recruits clathrin which provides the scaffold for theinvagination of the membrane forming a coated pit Fissionof the vesicle requires the activity of the GTPase dynamin[85] whereas vesicle uncoating depends on recruitment ofthe chaperone Hsc70 by the nerve-specific auxilin or theubiquitous GAK [86]

COPII- and COPI-coated vesicles are morphologicallyvery similar They are 50ndash60 nm in diameter with a 10 nm-thick coat However their composition location and role intransport differ The COPII coat is formed of five proteinsSec23 Sec24 Sec13 Sec 31 and the GTPase Sar1 [87 88]These proteins are soluble in the cytosol but associated toform coated buds at the ER Sar1 is the first componentrecruited in ER membranes This binding depends on theactivation of this GTPase by Sec12 a guanine nucleotideexchange factor (GEF) present in ER membranes [89] Sar1recruits the Sec23Sec24 heterodimer and then the Sec13Sec31 complex [90] During this process some proteins areselectively recruited in COPII vesicles [91] whereas othersenter unspecifically a process known as bulk flow [92] Thesize of the COPII vesicles can be adapted to a bulky cargoTANGO 1 is an adaptor protein that helps collagen VII toenter into vesicles [93] Recently it has been shown that ubiq-uitination of Sec31 regulated the formation of large COPIIvesicles [94] The role of COPII in ER-to-Golgi transport iswell established In specific places of the ER the ER exit sitesthis coat complex drives the formation of free coated vesiclescontaining cargoThese are quickly uncoated and fuse to eachother to form the so-called endoplasmic reticulum-Golgiintermediate compartment (ERGIC) or vesicular-tubularaggregates (VTCs) [95] This compartment is formed oftubulovesicular elements located close to the GC and dis-tributed throughout the cell and is associated to ER exit sites[96] This compartment was initially identified because thecargo accumulated in these elements when cells are culturedat low temperature (15∘C) [97 98] At the ERGIC the COPIcoat mediates the recycling of proteins back to the ER whileanterograde cargo is separated and concentrated It is notclear whether the ERGIC is a stable and static compartmentor conversely whether it works as a carrier [99] The factthat the proteins associated with this compartment are notresident but cycling between the ER and Golgi argues againstthe idea that it is a stable compartment This is the casewith ERGIC-53 a type I transmembrane protein of the lectinfamily which is the prototypical marker of this compartment[100] Anyway ERGIC elements or ERGIC-derived carriersmove to theGolgi area along themicrotubule track and therethey may fuse to each other to form the CGN or converselyfuse with a preexisting cisterna [101]

COPI-coated vesicles are found in peripheral and cen-tral ERGIC elements cis and lateral Golgi sides [80] and

occasionally at the trans-Golgi sideTGN [102] COPI-coatedbuds are observed at the lateral rims of cisternae decreasingin number in a cis to trans direction [28] COPI and clathrin-coated areas have been observed in immature secretorygranules [92] The function of the COPI coat in the Golgi-to-ER retrograde transport of soluble and membrane pro-teins has been convincingly demonstrated [103] Howeverthere are retrograde routes to the ER independent of COPI[104] COPI has also been associated with the anterogradeand retrograde intra-Golgi transport of cargo and residentenzymes respectively although this role remains highly con-troversial (see below) COPI coats are also involved in Golgifragmentation duringmitosis Golgi positioning lipid home-ostasis and endocytic routes [105] It is possible that thereare several subpopulations of COPI vesicles with differentcompositions and locations each carrying out its specificfunctions [106] The discovery and characterization of COPIvesicles data from the early 1980s when transport intermedi-ates were analyzed in cell-free experiments incubatingGolgi-enriched membranes with cytosol and GTP120574S [107 108]COPI coats are formed of seven subunits (120572 120573 1205731015840 120574 120575 120576120577-COP) assembled in the cytosol where they form a complexnamed coatomer [109] and the small GTPase ARF1 [110]ARF1 cycles between GDP- and GTP-bound forms [111]GTP-bound ARF1 binds to membranes and recruits thecoatomer en bloc resulting in membrane deformation Likeall small GTPases the activity of ARF1 is regulated by guaninenucleotide exchange factors (GEPs) and GTPase-activatingprotein (GAP) GEF catalyzes the exchange ofGDPwithGTPGolgi-associated BFA-resistant protein (GBF1) is the majorGEF for ARF1 during COPI vesicle formation in the Golgimembranes and is the target of the drug brefeldin A [112 113]Brefeldin A blocks the ARF1-GEF complex inhibiting theformation of ARF1-GTP and triggering Golgi disassemblyARFGAP proteins stimulate the GTP hydrolysis of ARFwhich has low intrinsic GTPase activity [114] It has beenpostulated that this reaction triggers uncoating [115] butthis point is under discussion [116] The proteins BARS andendophilinB seem to be necessary for the fission of COPIvesicles Interestingly ARFs have a role in the recruitmentand activation of lipid-modifying enzymes In additionARFGAP1 the first identified GAP for ARF1 is a membranecurvature sensor [117] Cargo inclusion requires GTP hydrol-ysis [118] For cargo sorting coatomer recognizes dibasicsequences [105 119] Many transmembrane proteins trans-ported into COPI vesicles bear dilysine motifs at their C-terminus [120] including ERGIC-53 [121] The coatomersubunits 120572- and 1205731015840-COP bind this signal directly [122] Thep24 family of proteins (23-24 kD transmembrane proteins)are recruited by direct interaction of their cytoplasmic tailwhich contains phenylalanine- and dilysine-based signals tocoatomer [123] However not all cargo incorporated in COPIvesicles have this sorting signal and may require adaptorsOne example is the KDEL receptor a transmembrane proteinmostly present in the cis Golgi and ERGIC that works as anadaptor for soluble proteins It interacts with the coatomerthrough a dilysine motif in the cytosolic tail whereas theluminal part interacts with soluble proteins bearing a K-D-E-L sequence (HDEL in yeast) a sequence found in many

ISRN Cell Biology 5

ER-resident proteins [124 125] In this way soluble proteinsthat have escaped from the ER are retrieved Glycosylationenzymes may also require cargo adaptors [105]

4 Transport Carriers Tubules andHeterogenic Elements

For a long time it was assumed that membrane traffic ismediated by coated vesicles Although they play a key role inmany steps of the transport it is possible that coated vesiclesjust represent a fraction of the intermediate transport carriersoperating in the secretory pathway [126] Tubular elementson the other hand have been associated with all steps ofthe secretory pathway (Polishchuk and Mironov [52]) Thetransport of soluble [127] and transmembrane [99] cargofrom pre-Golgi elements to the Golgi is mediated by tubulesTubules are 20 of the elements operating at the ER-Golgiinterface [128] Post-Golgi carriers may also have a tubularform [129 130] In fact the TGN itself is often formed by anetwork of branching tubules

Tubules are also involved in intra-Golgi transport TheGC is associated to an extensive network of 30 nm-thicktubules connected to the lateral edges of the stacked cisternaeand may extend a considerable distance from the stacks [57]Golgi tubules were already observed in the first electronmicroscopical observations of this organelle [25] Early stud-ies showed tubular elements emerging from the Golgi stackand TGN connected to cisternae or oriented towards thecytoplasm [26 27] Hermo and coworkers [131] describedtubular connections between cisternae in the cis side of theGolgi apparatus of spermatids Despite this tubules werealmost forgotten in the field for decades probably due tothe difficulty of identifying them in bidimensional electronmicrographs (they only can be identified in longitudinalsections) This was exacerbated cisternal maturation modelbeing abandoned in favor of the vesicular transport modelResearch into these elements increased with the introductionof the drug brefeldin A in the study of the GC This druginduces extensive tubulation of this organelle Although thissystem is artificial it has been postulated that brefeldinA exaggerates the natural process of retrograde transportHowever in contrast with normal conditions this transportoccurs only after the dissociation of COPI coats from theGC The development of new methodologies such as time-lapse confocal microscopy or electron tomography hasreintroduced the idea that tubules are transport intermedi-ates Time-lapse analysis of living cells has shown tubulesemerging from the GC [132] containing GFP-tagged residentenzymes [133] or cargo [101 134] Electron tomography con-firms that these elements are commonly associated to theGC [28 135] In NRK cells there are tubules that emergefrom cis and trans cisternae suggesting that they are involvedin incoming and outgoing Golgi trafficking Tubules maygrow from all cisternae and may extend towards CGN andTGN Interestingly one single cisterna may contain tubulesoriented to both cis and trans faces [28] In cells stimulatedto increase the secretion rate tubular connections betweencisternae are evident [136 137] but these connections

disappear when cargo has left the GC Thus tubules mightreplace vesicles when there is an excess of cargo Tubules mayalso participate in the recycling of Golgi resident enzymesUnder low temperature (15∘C) conditions many tubulesemerge from theGC ofHeLa cellsThese tubules are enrichedin Golgi-resident enzymes and a specific set of SNAREand Rab proteins associated with intra-Golgi transport andcontain neither retrograde nor anterograde cargo [138 139]This type of tubule can also be observed under physiologicalconditions and they are good candidates for being consideredtransport intermediates at the Golgi level Several types oftubules with different functions may well exist

The molecular machinery involved in the formation ofGolgi tubules is just beginning to be known Based onbrefeldin A experiments tubular formation at the GC hasbeen related with the loss of COPI coats [140 141] GTP-bound ARF1 is able to induce Golgi tubules by insertion ofthe amino-terminal amphipathic helix [142] Microtubule-associated motor proteins are sufficient to induce tubulesfrom Golgi membranes [143] Some lipidic species such asphosphatidic acid diacylglycerol and lysophosphatidic acidfavor the curvature of membranes Thus enzymes associatedwith lipid metabolism play a key role in tubular formationLysophosphatidic acid generated by the enzyme phospho-lipase A2 has been involved in the retrograde transportmediated by tubules [144 145] Agonist and antagonist of thisenzyme increase or inhibit tubular formation respectivelyThis enzyme is involved in the formation of tubular continu-ities between cisternae [146] and tubular transport interme-diates at the TGN [147] The formation of transport carriersat the TGN is also diacylglycerol dependent This lipid isnecessary to recruit protein kinaseD a regulator of the fissionof transport carriers [54 148] Diacylglycerol has also beeninvolved in Golgi-to-ER retrograde transport mediated bytubules [149] Phosphatidic acid has been involved in intra-Golgi transport [150] Interestingly two lipid-modifyingenzymes lysophosphatidic acid acyltransferase-120574 and phos-pholipase A2-120572 which promote or inhibit COPI fissionrespectively work together regulating the morphology ofGolgi carriers [151] On the other hand the morphology ofpre-Golgi tubules depends on the cargo [128] COPI coatsmicrotubules and associated motor proteins [152] and alsothe activity of ARF and phospholipase A2 [153]Thus similarmachineries may be operating at different levels of the secre-tory pathway Interestingly live cell imaging shows that pre-Golgi elements may change their morphology very quicklyfrom vesicular to tubular form and vice versa [152]

Apart from the tubules other transport intermediates ofheterogeneous morphology have been described Polishchukand coworkers [154] described the formation of large tubulo-saccular elements involved in the microtubule-dependenttransport from the TGN to the plasma membrane The samegroup has described heterogenic membranes involved in ER-to-Golgi transport [155] Very large pleiomorphicmembrane-bound elements have also been associated with transportin the early secretory pathway [156] It seems that thereare different classes of transport carriers depending of theamount or type of cargo

6 ISRN Cell Biology

5 Molecular Machinery

In recent decades a huge amount of information has beenaccumulated about the molecular machinery involved inthe regulation of the intercompartmental transport in thesecretory pathway Most data refer to vesicles as transportcarriers but it can be assumed that the same or similar mech-anisms operate for other carriers If the formation of vesiclesand the selection of cargo depends on the coatmachinery thespecific targeting and fusion of the carriers with the targetmembranes depends on tethering factors Rab and SNAREproteins and other accessory proteins [157] In a simplemodel the rabs on incoming vesicles recruit tethering factorswhich permits SNARE complex formation

SNAREs (soluble N-ethylmaleimide-sensitive factorattachment proteins receptors) proteins are involved indocking and the specific fusion of transport intermediateswith the targetmembranes [157ndash159]The SNAREs associatedwith vesicles (or other transport intermediates) and targetmembranes have been named v- and t-SNARE respectivelyThis terminology however is not useful for describinghomotypic fusion events Structurally SNAREs have beendivided into R- and Q-SNAREs according to the centralresidue (RGln or QArg resp) of the SNARE domain aconserved region of 60ndash70 residues found in all members ofthis family Although there are some exceptions v-SNAREand t-SNARE are R-SNARE and Q-SNARE respectivelyInteraction between one v-SNARE and twothree t-SNAREinduces the formation of the trans-SNARE complex whichcatalyzes the fusion of the membranes SNARE proteins aresufficient to drive membrane fusion so that they are con-sidered the minimal membrane fusion machinery Afterfusion a cis-SNARE complex is formed in the target mem-branes This complex is later disassembled by the action ofthe cytosolic proteins 120572-SNAP (soluble N-ethylmaleimide-sensitive factor attachment protein) and the ATPase NSF(N-ethylmaleimide-sensitive factor) Now v-SNARE can betransported back to the donor compartment to be reusedSeveral SNARE complexes working at the secretoryendo-cytic pathway have been identified In mammalian cellstwo SNARE complexes have been implicated in intra-Golgitransport [160] A complex is formed of v-SNARE GS15 andthe t-SNAREs syntaxin5 GOS28 and Ykt6 is involved inCOPI-dependent intra-Golgi transport The second complexis formed of syntaxin 5 membrin (GS27) ERS24Sec22 andrBet1 the last one acting as v-SNARE This second complexhas been also involved in the fusion ER-derived elementswith the cis-Golgi and possible intra-Golgi transport Thedistribution of these SNAREs across the Golgi stack isdifferent Thus in general the components of the first com-plex increase in concentration toward the trans side whereasthe components of the second complex decrease [161]supporting the idea that these complexes mediate transportevents in opposite directions Syntaxin 5 which is present inboth complexes is distributed homogeneously through thestack SNARE complex assembly is regulated by SM (Sec1Munc18) proteins a family of cytosolic proteins Sly1 I isthe only member of this family operating at the ER-Golgiarea where it interacts with syntaxin 5 and syntaxin 18 at

the Golgi and ER respectively and controls anterograde andretrograde transport between these compartments [162]

Rab proteins are a family of small GTPases regulatingmembrane transport by recruiting effector proteins [159 163]They are localized at the cytoplasmic face of secretory andendocytic compartments and carriers and they have beenimplicated in vesicle budding uncoating mobility and trans-port Rab switches between an active form (GTP-bound) anda cytosolic inactive form (GDP-bound) Rab proteins in theGTP-bound form are reversibly associated with membranesby geranylgeranyl groups recruiting a variety of effectorsincluding sorting adaptors tethering factors kinases phos-phatases and motor proteins [163] The replacement of GDPby GTP is facilitated by guanine nucleotide exchange factors(GEFs) and their low intrinsic GTPase activity is enhancedby GTPase-activating proteins (GAP) Further regulation ofthe GTPGDP state and membrane association is providedby GDP dissociation inhibitor (GDI) and GDI displacementfactors (GDFs) Rab protein is a large family includingmore than 60 members in humans and 11 in yeast whichare specifically associated with distinct compartments andtransport events [163] Thus Rab proteins have also beenassociated with the control of membrane identity by control-ling local levels of phosphoinositides which concomitantlymay recruit specific proteins to certain compartments [164]The association of Rab proteins with specific membranes isguided by Rab escort protein (REP) which presents newlysynthesized Rab to geranylgeranyl transferase before target-ing the membranes The Golgi-associated Rab family playinga key role in Golgi maintenance and functioning includesRab1 Rab2 Rab6 Rab33B Rab18 and Rab43 [165] Rab1 andRab2 are involved in ER-to-Golgi transport Rab 1 is also veryimportant for Golgi ribbon maintenance Interestingly thelevels of expression or the distribution of this small GTPaseis affected in neurological disorders that show fragmentationof the Golgi ribbon [166] (Rendon et al [167]) Rab6 andmore specifically the Rab6AArsquo isoform is the most widelystudiedGolgi-associated Rab protein [168] It is important formaintaining Golgi structure and also for regulating transportin and out of the GC including a COPI-independent Golgi-to-ER transport [169] It is also associated with post-Golgicarriers where it recruits motor proteins [170 171] and alsoregulates the docking and fusion with the plasma membrane[172] At the Golgi stack it anchors the tethering factorsnecessary for attaching incoming vesicles The organizationof the Golgi ribbon the regulation of the number of cisternaein the stack and transport of coated vesicles is also associatedwith Rab6 and effectors [173] Rab33B is localized specificallyin the medial Golgi [174] where it is involved in Golgi-to-ER retrograde transport [175] Interestingly Rab6A recruitsspecific GEF that also interacts with Rab33B connecting theseRabs in a Rab cascade [176]Most probably Rab6 and Rab33Bwork together in the regulation of intra-Golgi and Golgi-to-ER transport [165] Less information is available about Rab43and Rab18 but they are also thought to be involved in ER-Golgi trafficking and Golgi organization

Tethering factors are a group of membrane-associatedproteins or multisubunit complexes that link transport vesi-cles with the targetmembranes to ensure correct docking and

ISRN Cell Biology 7

fusion They have recently been classified into three classesoligomeric complexes that work as Rab effectors and bindsSNARE oligomeric complexes that function as GEFs for Rabproteins and finally coiled-coil tethers [177] Proteins withextensive coiled-coil domains are long allowing long distancetethering These bridges not only facilitate the formation ofSNARE complexes but also may provide an initial specificityfor membrane fusionMembers of this family associated withthe Golgi are called golgins [178] In addition to tetheringthey have a role in Golgi stacking and form the Golgi matrixThis family includes p115 and GM130 the first of which isassociated with COPI and COPII vesicles the ERGIC andcis-Golgi membranes This protein is believed to be involvedin tethering of COPII vesicles to ERGIC membranes and thetransport events from these elements to the cis-Golgi It is alsopossible that it participates in transport between cisternaeThe recruitment of p115 to membranes is Rab1 dependentIt also interacts with ER-Golgi SNAREs COG subunits andother coiled-coil proteins such as GM130 and giantin Thesignificance of the last interaction is not clear GM130 isanother coiled-coil protein associated with the cis Golgi Itinteracts with many proteins including GRASP65 p115 Rab1Rab2 Rab33b and sintaxin5 P115 and GM130 are membersof the family of golgins which were first identified as Golgi-localized autoantigens using antibodies derived from thesera of patients with a variety of autoimmune disorders Asindicated above GM130 and p115 are also components ofthe Golgi matrix Apart from their role as tethers togetherwith other members of the golgin family such as GRASP65and giantin they are involved in maintaining the stackedmorphology of the cisterna and the Golgi ribbon [179]

Multisubunit complexes associated with the Golgiinclude Dsl1 COG and TRAPPIII [177] Dsl1 is a three-unitcomplex involved in Golgi-to-ER transport where it acts astethering COPI vesicles It interacts and stabilizes an SNAREcomplex at the ER The conserved oligomeric Golgi (COG)complex formed of 8 subunits (Cog1ndash8) found at the cis- andmedial Golgi cisternae is believed to be involved in transportto the Golgi and intra-Golgi recycling of Golgi resident pro-teins [180] Components of this tethering factor interactwith COPI components SNARE proteins (syntaxin 5) andcoiled-coil tether (p115) and are the effectors of several Rabproteins (Rab1 Rab6) Transport protein particle (TRAPP) isanother multisubunit complex that works as tethering factor[181] Two complexes have been identified TRAPP I andTRAPPII which are involved in entry and exit from theGC tethering COPII and COPI vesicles respectively Theywork as GEF for Rab1 and the activation of this GTPasemight recruit other tethers (as p115 or COG) [177] Howeverthey do not interact directly with SNAREs It is possible thatthere is a cascade of tethering factors that facilitates cargotransport

6 Intra-Golgi Transport

The mode of transport across the GC remains controversialTwo main models have been proposed vesicular transportand cisternal maturation The first one proposes that Golgi

cisternae are static so that the cargo must move via vesiclesThe second model support that cisterna are dynamic struc-tures that move from the cis to trans Golgi sideThus accord-ing to this model the entire cisterna is the carrier In thesemodels COPI-coated vesicles are responsible for antero-grade and retrograde transport respectively (Figure 3) Sinceneither of these models explains all the experimental data acombination of the same models and new models have beenproposed (see below)

61 Vesicular Transport Model This model was launchedby Palade in 1975 and was widely accepted for many yearsbecause it provides a good explanation for the well-knowncompartmentalization of the Golgi resident enzymes In thismodel it is assumed that cisternae are stable compartmentsso that the cargo must leave one cisterna and move to thenext in order to advance through the stack This process ismediated by vesicles The model was strongly supported bythe discovery of COPI and COPII vesicles [182] COPI wereidentified in in vitro assays as being responsible for antero-grade transport between cisterna [107] In these cell-freeexperiments when the formation of COPI was inhibitedanterograde was blocked [183 184] On the other hand itwas clearly demonstrated that COPII vesicles are involved inER exit and transport to the GC [87] Soon it was assumedthat COPII and COPI vesicles act sequentially in the earlysecretory pathway that is ER-to-Golgi and intra-Golgitransport respectively However new experimental data castdoubt on the model First of all a clear role of COPI vesiclesin retrograde transport was demonstrated [120 185] To fitthese data with the model it was postulated that there weretwo types of COPI vesicles involved in anterograde and retro-grade transport at the Golgi stack [186] ldquoPercolatingrdquo COPIvesiclesmaymove bidirectionally up and down in the stack ina random way but allowing a net rate of flow of anterogradecargo in the cis-to-trans direction [187] However immuno-cytochemical [188] and proteomic [9] analysis of thesevesicles showed that they are mostly devoid of anterogradetransport markers Thus the role of COPI vesicles remainscontroversial [189] The small number of Golgi-associatedSNARE and Rab proteins also argues against multiple fusionevents between vesicles and every cisterna in the stacks Oneproblem is that this model does not explain the transport oflarge cargo such as procollagen (300 nm rigid rod) [190] oralgal scales (up to 15ndash2 120583m) [191] within 50ndash60 nm vesiclesInterestingly scales which are electron dense and can beeasily visualized are not observed within vesicles The exis-tence of megavesicles transporting large (gt400 nm) proteinaggregates has been described in an artificial system [192]but it is not clear that this a general mechanism used bynonmodified cells [190]

62 Cisternal Maturation Model This model was postu-lated in the early epoque of electron microscopy [193] andupdated as cisternal progression-maturation model [190194] According to this model cisternae are formed at thecis side of the GC by fusion of ER-derived membranes andthen these newly formed membranes move from the cis to

8 ISRN Cell Biology

Tubules Retrograde COPI vesicles

Cisternal maturation

Anterograde COPI vesicles

Retrograde COPI vesicles

Vesicular transport

Tubules

(a)

(b)

(c)

(d)

Figure 3 Putative role of COPI-coated vesicles and tubules according to vesicular transport and cisternal maturation models for intra-Golgitransport According to vesicular transport model cisternae are static Anterograde transport may be mediated by COPI-coated vesicles andtubular cisternal connections Another type of COPI-coated vesicles mediates retrograde transport (ie the retrieval of proteins that haveescaped from the endoplasmic reticulum) According to cisternal maturation model cisternae move from cis (a) to trans Golgi sides (d)COPI-coated vesicles and transient tubules may be involved in the recycling of Golgi resident proteins (retrograde transport)

the trans side where they become post-Golgi carriers Thusnewly formed cisterna gradually displaces older cisternaetowards the trans side In this model it is not necessary forthe cargo to leave the cisterna and the whole cisterna is takento act as a carrier This model explains the transport of largecargo and an analysis of procollagen transport fits this modelvery well [190] These large molecules are detected in largedistensions at the lateral edge of the cisterna in their transitthrough the stack These distensions are always connected

to the cisterna so that procollagen is not transported bylarge vesicles In contrast the model does not explain thepolarity of the stack and what happens with resident enzymeswhen cisternae disappear at the trans side To overcomethese problems it was assumed that Golgi resident enzymesare packed into COPI vesicles during cisternal progressionand transported backwards Thus Golgi enzymes are notlost but recycled in a trans-to-cis direction maintainingthe polarity of this organelle [195] The cisternae mature by

ISRN Cell Biology 9

acquiring and then losing specific Golgi-resident proteinsThe presence of Golgi resident enzymes in COPI vesicles hasbeen demonstrated [188] although their relative concentra-tion is controversial Life cell imaging studies in yeast stronglysupport this model In Saccharomyces cerevisiae the Golgiis not stacked so that individual cisterna can be analyzedseparately Using cis and trans Golgi markers it was directlydemonstrated that cisternae mature (ie the apparentlyconversion of one type of cisterna into another) [196 197]The cisternal maturation model seems to be more efficientgiven that it would seem easier to transport anterograde cargousing a large carrier (the cisterna) than to use many smallvesicles between adjacent cisternae and repeating this processseveral times until reaching the TGN It is also intuitive thatperi-Golgi vesicles should be restricted to more selective andsmaller trafficking the retrograde pathway

63 Alternative Models Given that none of these modelscompletely explains all the experimental data new modelshave been postulated although some of them are variationsof the two main models

Dual transport model one possibility is that these twomodels are not mutually exclusive but rather complementaryand working simultaneously [198] Cisternae may moveslowly whereas vesicles transport anterograde and retrogradecargo more rapidly Large molecules may use the cisternalmaturation mechanism while small molecules can be trans-ported using vesicular transport [186 198]

Rapid partitioning model This model is based on therapid partitioning of transmembrane cargo and residentenzymes between two lipid phases According to this modelthe GC works as a single compartment but contains pro-cessing and export domains [199] When the cargo reachesthe Golgi it associates with these domains and then leavesthe compartment from every level Again this model hasdifficulty in explaining the polarity of the cisternae and doesnot help visualize the Golgi stack as a single compartment

Kiss-and-runmodelThis model is based onmechanismsoperating in other systems such as endosomes and lysosomesThismodel proposes that two cisternaemay fuse to each otherthrough narrow tubules connecting their lumens transientlyand allowing the transit of cargo before separating [200] Inthis model anterograde transport and retrograde transportoccur simultaneously and a specific retrograde pathway is notnecessary This model may explain several aspects of Golgitransport including the transport of large molecules How-ever some assumptions of the model need to be confirmed(ig machinery and mechanisms for the fusion and fission ofconnections) It is also not clear how all the experimental dataabout the role of COPI coats in retrograde transport fit thismodel

Intra-Golgi transportmediated by tubulesThe absence ofcargo in COPI vesicles suggests that other transport interme-diates such as tubules may operate at the GC As mentionedabove tubules are a common structure surrounding the stackTubules may be involved in the anterograde movement ofcargo through this organelleThe ER and all cisternae may bedirectly connected by tubules and cargo might move along

the secretory pathway like food through the gut [201] Infact conditions that stimulated protein secretion increasethe number of tubular connections between cisternae [136137] Conversely tubules may establish transient connectionsbetween compartments helping COPI vesicles to transportGolgi enzymes retrogradely as indicated by the cisternalmaturation model [46] (Figure 3) Cisternal maturation inyeast occurs although slowly without COPI vesicles suggest-ing that tubules may replace them [197] Low temperature-induced Golgi tubules are enriched in Golgi enzymes andSNARE and Rab proteins involved in intra-Golgi transportwhereas they exclude other proteins associated with ER-Golgi transport [139] Whether the tubules found in thismodel are representative of the carriers involved in intra-Golgi transport remains to be established

7 Concluding Remarks

A century after the discovery of the ldquoapparato reticolareinternordquo [202] it is clear that no model for intra-Golgi trans-port explains all the experimental data But it is also true thatthe ldquohigh polarityrdquo that exits the field has stimulated intenseresearch Recently developed high-resolution methodologiesmay give important clues in this respect Of special interestis the analysis of the structure and composition of tubularand vesicular carriers High-resolution immunocytochemi-cal techniques in combination with electron tomography aswell as proteomic analysis of highly purified samples maysolve the problem or at least definitively reject some modelsIn the end it is possible that each cell type depending of itsspecial characteristics uses a givenmechanism of intra-Golgitransport It also remains possible that a single cell usesdifferent mechanisms of intra-Golgi transport depending onthe amount and type of cargo or its physiological statusMeanwhile cisternal maturation in combination with tubulartransient connections is a very attractive and intuitive modelthat seems to fit most experimental data

Acknowledgments

The work in this paper was supported by Grants fromthe Ministerio de Ciencia e Innovacion (Spain) ConsoliderCOAT (CSD2009-00016) and Fundacion Seneca de la Comu-nidadAutonoma de la Region deMurcia (04542GERM06)

References

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[2] W Nickel and C Rabouille ldquoMechanisms of regulated uncon-ventional protein secretionrdquo Nature Reviews Molecular CellBiology vol 10 no 2 pp 148ndash155 2009

[3] M G Farquhar and G E Palade ldquoThe Golgi apparatus (com-plex) (1954ndash1981) from artifact to center stagerdquo Journal of CellBiology vol 91 no 3 pp 77sndash103s 1981

[4] M G Farquhar and G E Palade ldquoThe Golgi apparatus 100years of progress and controversyrdquo Trends in Cell Biology vol8 no 1 pp 2ndash10 1998

10 ISRN Cell Biology

[5] C Wilson R Venditti L R Rega A Colanzi G DrsquoAngeloandM A De ldquoThe Golgi apparatus an organelle with multiplecomplex functionsrdquo Biochemical Journal vol 433 no 1 pp 1ndash92011

[6] J Lippincott-Schwartz E Snapp and A Kemvorthy ldquoStudyingprotein dynamics in living cellsrdquoNature Reviews Molecular CellBiology vol 2 no 6 pp 444ndash456 2001

[7] G Perinetti T Muller A Spaar R Polishchuk A Luini andA Egner ldquoCorrelation of 4Pi and electron microscopy to studytransport through single golgi stacks in living cells with superresolutionrdquo Traffic vol 10 no 4 pp 379ndash391 2009

[8] J Lippincott-Schwartz ldquoEmerging in vivo analyses of cellfunction using fluorescence imagingrdquo Annual Review of Bio-chemistry vol 80 pp 327ndash332 2011

[9] A Gilchrist C E Au J Hiding et al ldquoQuantitative proteomicsanalysis of the secretory pathwayrdquo Cell vol 127 no 6 pp 1265ndash1281 2006

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[14] R S Polishchuk E V Polishchuk P Marra et al ldquoCorrelativelight-electron microscopy reveals the tubular-saccular ultra-structure of carriers operating between Golgi apparatus andplasma membranerdquo Journal of Cell Biology vol 148 no 1 pp45ndash58 2000

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[21] M Anitei and B Hoflack ldquoExit from the trans-Golgi networkfrom molecules to mechanismsrdquo Current Opinion in Cell Biol-ogy vol 23 no 4 pp 443ndash451 2011

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[23] YWang and J Seemann ldquoGolgi biogenesisrdquoCold Spring HarborPerspectives in Biology vol 3 no 10 Article ID a005330 2011

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[28] M S Ladinsky D NMastronarde J RMcIntosh K E Howelland L A Staehelin ldquoGolgi structure in three dimensionsfunctional insights from the normal rat kidney cellrdquo Journal ofCell Biology vol 144 no 6 pp 1135ndash1149 1999

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ISRN Cell Biology 11

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[52] R S Polishchuk andA AMironov ldquoStructural aspects of Golgifunctionrdquo Cellular andMolecular Life Sciences vol 61 no 2 pp146ndash158 2004

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[54] F Bard and V Malhotra ldquoThe formation of TGN-to-plasma-membrane transport carriersrdquo Annual Review of Cell andDevelopmental Biology vol 22 pp 439ndash455 2006

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[57] H HMollenhauer andD J Morre ldquoThe tubular network of theGolgi apparatusrdquo Histochemistry and Cell Biology vol 109 no5-6 pp 533ndash543 1998

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12 ISRN Cell Biology

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[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

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[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

ISRN Cell Biology 3

tubular network connected to the stack and ER-derived pre-Golgi tubule-vesicular elements (see below) remain to beestablished

The trans-Golgi network (TGN) is located at the transside and is the place where proteins are sorted packed anddelivered to their final destination (endolysosomal systemapical or basolateral membranes secretion) It is also thecompartment where secretory and endocytic routes converge[47] In the TGN the final steps of glycosylation (includingsulfation and sialylation) serine-linked O-phosphorylationand the proteolytic processing of hormone precursors takeplace The organization of these membranes depends on celltype Usually the TGN is formed by a network of tubulo-vesicular membranes connected to one or two transmostcisternae while secretory cells containing immature secre-tory granules However the TGN may be an independentcompartment adjacent to the stack or conversely at somedistance from the same [48ndash51] The tubular component isextensive in cells with a well-developed lysosomal system andreduced in secretory cells The structural variability of theTGN may be due to its capacity to secrete different types ofcargo [52] and it is not clear whether this compartment isdivided into subdomains representing specialized exit sitesfor different destinations [22 53 54] Although function-ally and structurally connected the TGN and Golgi stackare different compartments as demonstrated in the use ofbrefeldin A This fungal drug induces the tubulation of bothcompartments but fusion with the endosomal system or ERrespectively [55] The pH of the TGN is more acidic than themedialtrans cisternae (658 and 591 resp) [56]

The structure of the GC is supported by the so-calledGolgi matrix a ribosome-free area surrounding the cisternaeand formedby structural proteinsThismatrix is visualized byelectron microscopy as small fibers connecting the cisternae[57] and also connecting the Golgi membranes and transportvesicles [58] A large number of Golgi matrix componentshave been identified including Golgi reassembly stackingproteins (GRASPs) and golgins [59] with GM130 being thefirst component identified [60] Some of the componentswere identified as autoantigens and others were isolated fromdetergent-insoluble salt-resistant Golgi fractions [61] Thesecomponents are very dynamic and cycle betweenmembrane-associated and a cytoplasmic forms process that dependson posttranslational modifications such as phosphorylationMatrix proteins are involved in the regulation of membranetraffic and the maintenance of the Golgi structure Morerecently the matrix has been related to microtubule organi-zation signaling and regulation of apoptosis and cell cycle[59]

The organization of the Golgi ribbon also depends onthe microtubule and actin cytoskeleton [62 63] In non-polarized cells stacks are distributed around the microtubuleorganization center (MTOC) usually close to the nucleus[64 65] However microtubules are not essential for otherfunctions such as glycosylation or global secretion Thefinal position of the ribbon and transport into or from thisorganelle is determined by the action of molecular motorsThemovement of transport carriers from the periphery to theGC at the cell centre is mediated by the minus-end-directed

motor dynein This motor and its cofactor dynactin areessential for maintenance of the perinuclear position of theGolgi ribbon [66] The movement in the opposite directionis mediated by the plus-ended-directed motor kinesin Inter-estingly the GC is able to nucleate and stabilize microtubulesacting as a secondary MTOC [67] The cis-Golgi proteinGMAP210 recruits 120574-tubulin to this organelle AKAP450 a 120574-tubulin-interaction centrosomal protein is also found at theGolgi after recruitment by GM130 [68] At the trans-Golgithe nucleation of microtubules depends on microtubule-binding proteins CLASPs which are recruited to the Golgimembranes through the golgin GCC185 [69] This processis necessary for polarized secretion and the maintenanceof the Golgi ribbon [70] On the other hand actin hasbeen associated with coated transport vesicles and buds [71]Golgi membranes also contain molecules such as Arp23N-WASP or cdc42 that trigger actin polymerization [72]Actin filaments and actin-associated proteins are involved inpost-Golgi [73] andGolgi-to-ER [74] transport Interestinglythe action of the microtubule and actin cytoskeletons iscoordinated [75] One of the factors involved in this link is theprotein WHAMM (WASP homology associated with actinmembrane and microtubules) which is present in the Golgiand pre-Golgi elements This protein has domains that bindactin-binding proteins such as profilin andArp23 a domainthat directly bind microtubules and a domain required tobind lipids [76] WHAMM regulates carrier morphologyduring intracellular transport [77]

3 Transport Carriers Vesicles

The stacks are surrounded by small vesicles of different sizesand many of them are coated For example in two adjacentstacks of NRK cells of the sim400 vesicles found one halfwere coated [28]Three different types of coat complexes havebeen identified and characterized in detail (COPI COPIIclathrin) although the existence of other coat complexescannot be rejected

Clathrin-coated vesicles were the first to be identified [7879] Both their size (100 nm) and the coat thickness (18 nm)are larger than in COP vesicles [80] Clathrin is mainlyinvolved in transport fromGCor from the plasmamembraneto the endolysosomal system [81] In the Golgi area clathrin-coated vesicles and buds are associated with the trans-mostGolgi cisterna and TGN [28] where it is involved in theexport of mannose-6-phosphate receptors carrying newlysynthesized lysosomal enzymes [82] Clathrin is a proteincomplex formed by three heavy and three light chains thatassemble to make a basket-like structure made up of pen-tagons and hexagons [83]Their association with membranesand the recruitment of cargo is mediated by adaptor com-plexes Clathrin binds a variety of adaptor complexes involvedin different transport events In humans four ubiquitouslyexpressed adaptor complexes (AP1-4) and three Golgi-localized 120574-ear-containing ARF-binding proteins (GGA1-3)have been identified AP2 is restricted to the plasma mem-brane where it is involved in endocytosis whereas GGAsand AP1-4 are located at the TGN andor in endosomes [17]At theTGNAP1 andCGAproteins recognize specific signals

4 ISRN Cell Biology

present in mannose-6-phosphate receptors and contribute tothe sorting of these receptors which their cargo hydrolysesinto clathrin-coated vesicles [82] AP1 AP3 and AP4 (in thiscase independently of clathrin) are involved in the sortingof lysosomal membrane proteins at the TGN In polarizedcells AP1 AP3 and AP4 are involved in the sorting of baso-lateral membrane proteins but probably through a clathrin-independent mechanism [84] The binding of cargo andadaptor recruits clathrin which provides the scaffold for theinvagination of the membrane forming a coated pit Fissionof the vesicle requires the activity of the GTPase dynamin[85] whereas vesicle uncoating depends on recruitment ofthe chaperone Hsc70 by the nerve-specific auxilin or theubiquitous GAK [86]

COPII- and COPI-coated vesicles are morphologicallyvery similar They are 50ndash60 nm in diameter with a 10 nm-thick coat However their composition location and role intransport differ The COPII coat is formed of five proteinsSec23 Sec24 Sec13 Sec 31 and the GTPase Sar1 [87 88]These proteins are soluble in the cytosol but associated toform coated buds at the ER Sar1 is the first componentrecruited in ER membranes This binding depends on theactivation of this GTPase by Sec12 a guanine nucleotideexchange factor (GEF) present in ER membranes [89] Sar1recruits the Sec23Sec24 heterodimer and then the Sec13Sec31 complex [90] During this process some proteins areselectively recruited in COPII vesicles [91] whereas othersenter unspecifically a process known as bulk flow [92] Thesize of the COPII vesicles can be adapted to a bulky cargoTANGO 1 is an adaptor protein that helps collagen VII toenter into vesicles [93] Recently it has been shown that ubiq-uitination of Sec31 regulated the formation of large COPIIvesicles [94] The role of COPII in ER-to-Golgi transport iswell established In specific places of the ER the ER exit sitesthis coat complex drives the formation of free coated vesiclescontaining cargoThese are quickly uncoated and fuse to eachother to form the so-called endoplasmic reticulum-Golgiintermediate compartment (ERGIC) or vesicular-tubularaggregates (VTCs) [95] This compartment is formed oftubulovesicular elements located close to the GC and dis-tributed throughout the cell and is associated to ER exit sites[96] This compartment was initially identified because thecargo accumulated in these elements when cells are culturedat low temperature (15∘C) [97 98] At the ERGIC the COPIcoat mediates the recycling of proteins back to the ER whileanterograde cargo is separated and concentrated It is notclear whether the ERGIC is a stable and static compartmentor conversely whether it works as a carrier [99] The factthat the proteins associated with this compartment are notresident but cycling between the ER and Golgi argues againstthe idea that it is a stable compartment This is the casewith ERGIC-53 a type I transmembrane protein of the lectinfamily which is the prototypical marker of this compartment[100] Anyway ERGIC elements or ERGIC-derived carriersmove to theGolgi area along themicrotubule track and therethey may fuse to each other to form the CGN or converselyfuse with a preexisting cisterna [101]

COPI-coated vesicles are found in peripheral and cen-tral ERGIC elements cis and lateral Golgi sides [80] and

occasionally at the trans-Golgi sideTGN [102] COPI-coatedbuds are observed at the lateral rims of cisternae decreasingin number in a cis to trans direction [28] COPI and clathrin-coated areas have been observed in immature secretorygranules [92] The function of the COPI coat in the Golgi-to-ER retrograde transport of soluble and membrane pro-teins has been convincingly demonstrated [103] Howeverthere are retrograde routes to the ER independent of COPI[104] COPI has also been associated with the anterogradeand retrograde intra-Golgi transport of cargo and residentenzymes respectively although this role remains highly con-troversial (see below) COPI coats are also involved in Golgifragmentation duringmitosis Golgi positioning lipid home-ostasis and endocytic routes [105] It is possible that thereare several subpopulations of COPI vesicles with differentcompositions and locations each carrying out its specificfunctions [106] The discovery and characterization of COPIvesicles data from the early 1980s when transport intermedi-ates were analyzed in cell-free experiments incubatingGolgi-enriched membranes with cytosol and GTP120574S [107 108]COPI coats are formed of seven subunits (120572 120573 1205731015840 120574 120575 120576120577-COP) assembled in the cytosol where they form a complexnamed coatomer [109] and the small GTPase ARF1 [110]ARF1 cycles between GDP- and GTP-bound forms [111]GTP-bound ARF1 binds to membranes and recruits thecoatomer en bloc resulting in membrane deformation Likeall small GTPases the activity of ARF1 is regulated by guaninenucleotide exchange factors (GEPs) and GTPase-activatingprotein (GAP) GEF catalyzes the exchange ofGDPwithGTPGolgi-associated BFA-resistant protein (GBF1) is the majorGEF for ARF1 during COPI vesicle formation in the Golgimembranes and is the target of the drug brefeldin A [112 113]Brefeldin A blocks the ARF1-GEF complex inhibiting theformation of ARF1-GTP and triggering Golgi disassemblyARFGAP proteins stimulate the GTP hydrolysis of ARFwhich has low intrinsic GTPase activity [114] It has beenpostulated that this reaction triggers uncoating [115] butthis point is under discussion [116] The proteins BARS andendophilinB seem to be necessary for the fission of COPIvesicles Interestingly ARFs have a role in the recruitmentand activation of lipid-modifying enzymes In additionARFGAP1 the first identified GAP for ARF1 is a membranecurvature sensor [117] Cargo inclusion requires GTP hydrol-ysis [118] For cargo sorting coatomer recognizes dibasicsequences [105 119] Many transmembrane proteins trans-ported into COPI vesicles bear dilysine motifs at their C-terminus [120] including ERGIC-53 [121] The coatomersubunits 120572- and 1205731015840-COP bind this signal directly [122] Thep24 family of proteins (23-24 kD transmembrane proteins)are recruited by direct interaction of their cytoplasmic tailwhich contains phenylalanine- and dilysine-based signals tocoatomer [123] However not all cargo incorporated in COPIvesicles have this sorting signal and may require adaptorsOne example is the KDEL receptor a transmembrane proteinmostly present in the cis Golgi and ERGIC that works as anadaptor for soluble proteins It interacts with the coatomerthrough a dilysine motif in the cytosolic tail whereas theluminal part interacts with soluble proteins bearing a K-D-E-L sequence (HDEL in yeast) a sequence found in many

ISRN Cell Biology 5

ER-resident proteins [124 125] In this way soluble proteinsthat have escaped from the ER are retrieved Glycosylationenzymes may also require cargo adaptors [105]

4 Transport Carriers Tubules andHeterogenic Elements

For a long time it was assumed that membrane traffic ismediated by coated vesicles Although they play a key role inmany steps of the transport it is possible that coated vesiclesjust represent a fraction of the intermediate transport carriersoperating in the secretory pathway [126] Tubular elementson the other hand have been associated with all steps ofthe secretory pathway (Polishchuk and Mironov [52]) Thetransport of soluble [127] and transmembrane [99] cargofrom pre-Golgi elements to the Golgi is mediated by tubulesTubules are 20 of the elements operating at the ER-Golgiinterface [128] Post-Golgi carriers may also have a tubularform [129 130] In fact the TGN itself is often formed by anetwork of branching tubules

Tubules are also involved in intra-Golgi transport TheGC is associated to an extensive network of 30 nm-thicktubules connected to the lateral edges of the stacked cisternaeand may extend a considerable distance from the stacks [57]Golgi tubules were already observed in the first electronmicroscopical observations of this organelle [25] Early stud-ies showed tubular elements emerging from the Golgi stackand TGN connected to cisternae or oriented towards thecytoplasm [26 27] Hermo and coworkers [131] describedtubular connections between cisternae in the cis side of theGolgi apparatus of spermatids Despite this tubules werealmost forgotten in the field for decades probably due tothe difficulty of identifying them in bidimensional electronmicrographs (they only can be identified in longitudinalsections) This was exacerbated cisternal maturation modelbeing abandoned in favor of the vesicular transport modelResearch into these elements increased with the introductionof the drug brefeldin A in the study of the GC This druginduces extensive tubulation of this organelle Although thissystem is artificial it has been postulated that brefeldinA exaggerates the natural process of retrograde transportHowever in contrast with normal conditions this transportoccurs only after the dissociation of COPI coats from theGC The development of new methodologies such as time-lapse confocal microscopy or electron tomography hasreintroduced the idea that tubules are transport intermedi-ates Time-lapse analysis of living cells has shown tubulesemerging from the GC [132] containing GFP-tagged residentenzymes [133] or cargo [101 134] Electron tomography con-firms that these elements are commonly associated to theGC [28 135] In NRK cells there are tubules that emergefrom cis and trans cisternae suggesting that they are involvedin incoming and outgoing Golgi trafficking Tubules maygrow from all cisternae and may extend towards CGN andTGN Interestingly one single cisterna may contain tubulesoriented to both cis and trans faces [28] In cells stimulatedto increase the secretion rate tubular connections betweencisternae are evident [136 137] but these connections

disappear when cargo has left the GC Thus tubules mightreplace vesicles when there is an excess of cargo Tubules mayalso participate in the recycling of Golgi resident enzymesUnder low temperature (15∘C) conditions many tubulesemerge from theGC ofHeLa cellsThese tubules are enrichedin Golgi-resident enzymes and a specific set of SNAREand Rab proteins associated with intra-Golgi transport andcontain neither retrograde nor anterograde cargo [138 139]This type of tubule can also be observed under physiologicalconditions and they are good candidates for being consideredtransport intermediates at the Golgi level Several types oftubules with different functions may well exist

The molecular machinery involved in the formation ofGolgi tubules is just beginning to be known Based onbrefeldin A experiments tubular formation at the GC hasbeen related with the loss of COPI coats [140 141] GTP-bound ARF1 is able to induce Golgi tubules by insertion ofthe amino-terminal amphipathic helix [142] Microtubule-associated motor proteins are sufficient to induce tubulesfrom Golgi membranes [143] Some lipidic species such asphosphatidic acid diacylglycerol and lysophosphatidic acidfavor the curvature of membranes Thus enzymes associatedwith lipid metabolism play a key role in tubular formationLysophosphatidic acid generated by the enzyme phospho-lipase A2 has been involved in the retrograde transportmediated by tubules [144 145] Agonist and antagonist of thisenzyme increase or inhibit tubular formation respectivelyThis enzyme is involved in the formation of tubular continu-ities between cisternae [146] and tubular transport interme-diates at the TGN [147] The formation of transport carriersat the TGN is also diacylglycerol dependent This lipid isnecessary to recruit protein kinaseD a regulator of the fissionof transport carriers [54 148] Diacylglycerol has also beeninvolved in Golgi-to-ER retrograde transport mediated bytubules [149] Phosphatidic acid has been involved in intra-Golgi transport [150] Interestingly two lipid-modifyingenzymes lysophosphatidic acid acyltransferase-120574 and phos-pholipase A2-120572 which promote or inhibit COPI fissionrespectively work together regulating the morphology ofGolgi carriers [151] On the other hand the morphology ofpre-Golgi tubules depends on the cargo [128] COPI coatsmicrotubules and associated motor proteins [152] and alsothe activity of ARF and phospholipase A2 [153]Thus similarmachineries may be operating at different levels of the secre-tory pathway Interestingly live cell imaging shows that pre-Golgi elements may change their morphology very quicklyfrom vesicular to tubular form and vice versa [152]

Apart from the tubules other transport intermediates ofheterogeneous morphology have been described Polishchukand coworkers [154] described the formation of large tubulo-saccular elements involved in the microtubule-dependenttransport from the TGN to the plasma membrane The samegroup has described heterogenic membranes involved in ER-to-Golgi transport [155] Very large pleiomorphicmembrane-bound elements have also been associated with transportin the early secretory pathway [156] It seems that thereare different classes of transport carriers depending of theamount or type of cargo

6 ISRN Cell Biology

5 Molecular Machinery

In recent decades a huge amount of information has beenaccumulated about the molecular machinery involved inthe regulation of the intercompartmental transport in thesecretory pathway Most data refer to vesicles as transportcarriers but it can be assumed that the same or similar mech-anisms operate for other carriers If the formation of vesiclesand the selection of cargo depends on the coatmachinery thespecific targeting and fusion of the carriers with the targetmembranes depends on tethering factors Rab and SNAREproteins and other accessory proteins [157] In a simplemodel the rabs on incoming vesicles recruit tethering factorswhich permits SNARE complex formation

SNAREs (soluble N-ethylmaleimide-sensitive factorattachment proteins receptors) proteins are involved indocking and the specific fusion of transport intermediateswith the targetmembranes [157ndash159]The SNAREs associatedwith vesicles (or other transport intermediates) and targetmembranes have been named v- and t-SNARE respectivelyThis terminology however is not useful for describinghomotypic fusion events Structurally SNAREs have beendivided into R- and Q-SNAREs according to the centralresidue (RGln or QArg resp) of the SNARE domain aconserved region of 60ndash70 residues found in all members ofthis family Although there are some exceptions v-SNAREand t-SNARE are R-SNARE and Q-SNARE respectivelyInteraction between one v-SNARE and twothree t-SNAREinduces the formation of the trans-SNARE complex whichcatalyzes the fusion of the membranes SNARE proteins aresufficient to drive membrane fusion so that they are con-sidered the minimal membrane fusion machinery Afterfusion a cis-SNARE complex is formed in the target mem-branes This complex is later disassembled by the action ofthe cytosolic proteins 120572-SNAP (soluble N-ethylmaleimide-sensitive factor attachment protein) and the ATPase NSF(N-ethylmaleimide-sensitive factor) Now v-SNARE can betransported back to the donor compartment to be reusedSeveral SNARE complexes working at the secretoryendo-cytic pathway have been identified In mammalian cellstwo SNARE complexes have been implicated in intra-Golgitransport [160] A complex is formed of v-SNARE GS15 andthe t-SNAREs syntaxin5 GOS28 and Ykt6 is involved inCOPI-dependent intra-Golgi transport The second complexis formed of syntaxin 5 membrin (GS27) ERS24Sec22 andrBet1 the last one acting as v-SNARE This second complexhas been also involved in the fusion ER-derived elementswith the cis-Golgi and possible intra-Golgi transport Thedistribution of these SNAREs across the Golgi stack isdifferent Thus in general the components of the first com-plex increase in concentration toward the trans side whereasthe components of the second complex decrease [161]supporting the idea that these complexes mediate transportevents in opposite directions Syntaxin 5 which is present inboth complexes is distributed homogeneously through thestack SNARE complex assembly is regulated by SM (Sec1Munc18) proteins a family of cytosolic proteins Sly1 I isthe only member of this family operating at the ER-Golgiarea where it interacts with syntaxin 5 and syntaxin 18 at

the Golgi and ER respectively and controls anterograde andretrograde transport between these compartments [162]

Rab proteins are a family of small GTPases regulatingmembrane transport by recruiting effector proteins [159 163]They are localized at the cytoplasmic face of secretory andendocytic compartments and carriers and they have beenimplicated in vesicle budding uncoating mobility and trans-port Rab switches between an active form (GTP-bound) anda cytosolic inactive form (GDP-bound) Rab proteins in theGTP-bound form are reversibly associated with membranesby geranylgeranyl groups recruiting a variety of effectorsincluding sorting adaptors tethering factors kinases phos-phatases and motor proteins [163] The replacement of GDPby GTP is facilitated by guanine nucleotide exchange factors(GEFs) and their low intrinsic GTPase activity is enhancedby GTPase-activating proteins (GAP) Further regulation ofthe GTPGDP state and membrane association is providedby GDP dissociation inhibitor (GDI) and GDI displacementfactors (GDFs) Rab protein is a large family includingmore than 60 members in humans and 11 in yeast whichare specifically associated with distinct compartments andtransport events [163] Thus Rab proteins have also beenassociated with the control of membrane identity by control-ling local levels of phosphoinositides which concomitantlymay recruit specific proteins to certain compartments [164]The association of Rab proteins with specific membranes isguided by Rab escort protein (REP) which presents newlysynthesized Rab to geranylgeranyl transferase before target-ing the membranes The Golgi-associated Rab family playinga key role in Golgi maintenance and functioning includesRab1 Rab2 Rab6 Rab33B Rab18 and Rab43 [165] Rab1 andRab2 are involved in ER-to-Golgi transport Rab 1 is also veryimportant for Golgi ribbon maintenance Interestingly thelevels of expression or the distribution of this small GTPaseis affected in neurological disorders that show fragmentationof the Golgi ribbon [166] (Rendon et al [167]) Rab6 andmore specifically the Rab6AArsquo isoform is the most widelystudiedGolgi-associated Rab protein [168] It is important formaintaining Golgi structure and also for regulating transportin and out of the GC including a COPI-independent Golgi-to-ER transport [169] It is also associated with post-Golgicarriers where it recruits motor proteins [170 171] and alsoregulates the docking and fusion with the plasma membrane[172] At the Golgi stack it anchors the tethering factorsnecessary for attaching incoming vesicles The organizationof the Golgi ribbon the regulation of the number of cisternaein the stack and transport of coated vesicles is also associatedwith Rab6 and effectors [173] Rab33B is localized specificallyin the medial Golgi [174] where it is involved in Golgi-to-ER retrograde transport [175] Interestingly Rab6A recruitsspecific GEF that also interacts with Rab33B connecting theseRabs in a Rab cascade [176]Most probably Rab6 and Rab33Bwork together in the regulation of intra-Golgi and Golgi-to-ER transport [165] Less information is available about Rab43and Rab18 but they are also thought to be involved in ER-Golgi trafficking and Golgi organization

Tethering factors are a group of membrane-associatedproteins or multisubunit complexes that link transport vesi-cles with the targetmembranes to ensure correct docking and

ISRN Cell Biology 7

fusion They have recently been classified into three classesoligomeric complexes that work as Rab effectors and bindsSNARE oligomeric complexes that function as GEFs for Rabproteins and finally coiled-coil tethers [177] Proteins withextensive coiled-coil domains are long allowing long distancetethering These bridges not only facilitate the formation ofSNARE complexes but also may provide an initial specificityfor membrane fusionMembers of this family associated withthe Golgi are called golgins [178] In addition to tetheringthey have a role in Golgi stacking and form the Golgi matrixThis family includes p115 and GM130 the first of which isassociated with COPI and COPII vesicles the ERGIC andcis-Golgi membranes This protein is believed to be involvedin tethering of COPII vesicles to ERGIC membranes and thetransport events from these elements to the cis-Golgi It is alsopossible that it participates in transport between cisternaeThe recruitment of p115 to membranes is Rab1 dependentIt also interacts with ER-Golgi SNAREs COG subunits andother coiled-coil proteins such as GM130 and giantin Thesignificance of the last interaction is not clear GM130 isanother coiled-coil protein associated with the cis Golgi Itinteracts with many proteins including GRASP65 p115 Rab1Rab2 Rab33b and sintaxin5 P115 and GM130 are membersof the family of golgins which were first identified as Golgi-localized autoantigens using antibodies derived from thesera of patients with a variety of autoimmune disorders Asindicated above GM130 and p115 are also components ofthe Golgi matrix Apart from their role as tethers togetherwith other members of the golgin family such as GRASP65and giantin they are involved in maintaining the stackedmorphology of the cisterna and the Golgi ribbon [179]

Multisubunit complexes associated with the Golgiinclude Dsl1 COG and TRAPPIII [177] Dsl1 is a three-unitcomplex involved in Golgi-to-ER transport where it acts astethering COPI vesicles It interacts and stabilizes an SNAREcomplex at the ER The conserved oligomeric Golgi (COG)complex formed of 8 subunits (Cog1ndash8) found at the cis- andmedial Golgi cisternae is believed to be involved in transportto the Golgi and intra-Golgi recycling of Golgi resident pro-teins [180] Components of this tethering factor interactwith COPI components SNARE proteins (syntaxin 5) andcoiled-coil tether (p115) and are the effectors of several Rabproteins (Rab1 Rab6) Transport protein particle (TRAPP) isanother multisubunit complex that works as tethering factor[181] Two complexes have been identified TRAPP I andTRAPPII which are involved in entry and exit from theGC tethering COPII and COPI vesicles respectively Theywork as GEF for Rab1 and the activation of this GTPasemight recruit other tethers (as p115 or COG) [177] Howeverthey do not interact directly with SNAREs It is possible thatthere is a cascade of tethering factors that facilitates cargotransport

6 Intra-Golgi Transport

The mode of transport across the GC remains controversialTwo main models have been proposed vesicular transportand cisternal maturation The first one proposes that Golgi

cisternae are static so that the cargo must move via vesiclesThe second model support that cisterna are dynamic struc-tures that move from the cis to trans Golgi sideThus accord-ing to this model the entire cisterna is the carrier In thesemodels COPI-coated vesicles are responsible for antero-grade and retrograde transport respectively (Figure 3) Sinceneither of these models explains all the experimental data acombination of the same models and new models have beenproposed (see below)

61 Vesicular Transport Model This model was launchedby Palade in 1975 and was widely accepted for many yearsbecause it provides a good explanation for the well-knowncompartmentalization of the Golgi resident enzymes In thismodel it is assumed that cisternae are stable compartmentsso that the cargo must leave one cisterna and move to thenext in order to advance through the stack This process ismediated by vesicles The model was strongly supported bythe discovery of COPI and COPII vesicles [182] COPI wereidentified in in vitro assays as being responsible for antero-grade transport between cisterna [107] In these cell-freeexperiments when the formation of COPI was inhibitedanterograde was blocked [183 184] On the other hand itwas clearly demonstrated that COPII vesicles are involved inER exit and transport to the GC [87] Soon it was assumedthat COPII and COPI vesicles act sequentially in the earlysecretory pathway that is ER-to-Golgi and intra-Golgitransport respectively However new experimental data castdoubt on the model First of all a clear role of COPI vesiclesin retrograde transport was demonstrated [120 185] To fitthese data with the model it was postulated that there weretwo types of COPI vesicles involved in anterograde and retro-grade transport at the Golgi stack [186] ldquoPercolatingrdquo COPIvesiclesmaymove bidirectionally up and down in the stack ina random way but allowing a net rate of flow of anterogradecargo in the cis-to-trans direction [187] However immuno-cytochemical [188] and proteomic [9] analysis of thesevesicles showed that they are mostly devoid of anterogradetransport markers Thus the role of COPI vesicles remainscontroversial [189] The small number of Golgi-associatedSNARE and Rab proteins also argues against multiple fusionevents between vesicles and every cisterna in the stacks Oneproblem is that this model does not explain the transport oflarge cargo such as procollagen (300 nm rigid rod) [190] oralgal scales (up to 15ndash2 120583m) [191] within 50ndash60 nm vesiclesInterestingly scales which are electron dense and can beeasily visualized are not observed within vesicles The exis-tence of megavesicles transporting large (gt400 nm) proteinaggregates has been described in an artificial system [192]but it is not clear that this a general mechanism used bynonmodified cells [190]

62 Cisternal Maturation Model This model was postu-lated in the early epoque of electron microscopy [193] andupdated as cisternal progression-maturation model [190194] According to this model cisternae are formed at thecis side of the GC by fusion of ER-derived membranes andthen these newly formed membranes move from the cis to

8 ISRN Cell Biology

Tubules Retrograde COPI vesicles

Cisternal maturation

Anterograde COPI vesicles

Retrograde COPI vesicles

Vesicular transport

Tubules

(a)

(b)

(c)

(d)

Figure 3 Putative role of COPI-coated vesicles and tubules according to vesicular transport and cisternal maturation models for intra-Golgitransport According to vesicular transport model cisternae are static Anterograde transport may be mediated by COPI-coated vesicles andtubular cisternal connections Another type of COPI-coated vesicles mediates retrograde transport (ie the retrieval of proteins that haveescaped from the endoplasmic reticulum) According to cisternal maturation model cisternae move from cis (a) to trans Golgi sides (d)COPI-coated vesicles and transient tubules may be involved in the recycling of Golgi resident proteins (retrograde transport)

the trans side where they become post-Golgi carriers Thusnewly formed cisterna gradually displaces older cisternaetowards the trans side In this model it is not necessary forthe cargo to leave the cisterna and the whole cisterna is takento act as a carrier This model explains the transport of largecargo and an analysis of procollagen transport fits this modelvery well [190] These large molecules are detected in largedistensions at the lateral edge of the cisterna in their transitthrough the stack These distensions are always connected

to the cisterna so that procollagen is not transported bylarge vesicles In contrast the model does not explain thepolarity of the stack and what happens with resident enzymeswhen cisternae disappear at the trans side To overcomethese problems it was assumed that Golgi resident enzymesare packed into COPI vesicles during cisternal progressionand transported backwards Thus Golgi enzymes are notlost but recycled in a trans-to-cis direction maintainingthe polarity of this organelle [195] The cisternae mature by

ISRN Cell Biology 9

acquiring and then losing specific Golgi-resident proteinsThe presence of Golgi resident enzymes in COPI vesicles hasbeen demonstrated [188] although their relative concentra-tion is controversial Life cell imaging studies in yeast stronglysupport this model In Saccharomyces cerevisiae the Golgiis not stacked so that individual cisterna can be analyzedseparately Using cis and trans Golgi markers it was directlydemonstrated that cisternae mature (ie the apparentlyconversion of one type of cisterna into another) [196 197]The cisternal maturation model seems to be more efficientgiven that it would seem easier to transport anterograde cargousing a large carrier (the cisterna) than to use many smallvesicles between adjacent cisternae and repeating this processseveral times until reaching the TGN It is also intuitive thatperi-Golgi vesicles should be restricted to more selective andsmaller trafficking the retrograde pathway

63 Alternative Models Given that none of these modelscompletely explains all the experimental data new modelshave been postulated although some of them are variationsof the two main models

Dual transport model one possibility is that these twomodels are not mutually exclusive but rather complementaryand working simultaneously [198] Cisternae may moveslowly whereas vesicles transport anterograde and retrogradecargo more rapidly Large molecules may use the cisternalmaturation mechanism while small molecules can be trans-ported using vesicular transport [186 198]

Rapid partitioning model This model is based on therapid partitioning of transmembrane cargo and residentenzymes between two lipid phases According to this modelthe GC works as a single compartment but contains pro-cessing and export domains [199] When the cargo reachesthe Golgi it associates with these domains and then leavesthe compartment from every level Again this model hasdifficulty in explaining the polarity of the cisternae and doesnot help visualize the Golgi stack as a single compartment

Kiss-and-runmodelThis model is based onmechanismsoperating in other systems such as endosomes and lysosomesThismodel proposes that two cisternaemay fuse to each otherthrough narrow tubules connecting their lumens transientlyand allowing the transit of cargo before separating [200] Inthis model anterograde transport and retrograde transportoccur simultaneously and a specific retrograde pathway is notnecessary This model may explain several aspects of Golgitransport including the transport of large molecules How-ever some assumptions of the model need to be confirmed(ig machinery and mechanisms for the fusion and fission ofconnections) It is also not clear how all the experimental dataabout the role of COPI coats in retrograde transport fit thismodel

Intra-Golgi transportmediated by tubulesThe absence ofcargo in COPI vesicles suggests that other transport interme-diates such as tubules may operate at the GC As mentionedabove tubules are a common structure surrounding the stackTubules may be involved in the anterograde movement ofcargo through this organelleThe ER and all cisternae may bedirectly connected by tubules and cargo might move along

the secretory pathway like food through the gut [201] Infact conditions that stimulated protein secretion increasethe number of tubular connections between cisternae [136137] Conversely tubules may establish transient connectionsbetween compartments helping COPI vesicles to transportGolgi enzymes retrogradely as indicated by the cisternalmaturation model [46] (Figure 3) Cisternal maturation inyeast occurs although slowly without COPI vesicles suggest-ing that tubules may replace them [197] Low temperature-induced Golgi tubules are enriched in Golgi enzymes andSNARE and Rab proteins involved in intra-Golgi transportwhereas they exclude other proteins associated with ER-Golgi transport [139] Whether the tubules found in thismodel are representative of the carriers involved in intra-Golgi transport remains to be established

7 Concluding Remarks

A century after the discovery of the ldquoapparato reticolareinternordquo [202] it is clear that no model for intra-Golgi trans-port explains all the experimental data But it is also true thatthe ldquohigh polarityrdquo that exits the field has stimulated intenseresearch Recently developed high-resolution methodologiesmay give important clues in this respect Of special interestis the analysis of the structure and composition of tubularand vesicular carriers High-resolution immunocytochemi-cal techniques in combination with electron tomography aswell as proteomic analysis of highly purified samples maysolve the problem or at least definitively reject some modelsIn the end it is possible that each cell type depending of itsspecial characteristics uses a givenmechanism of intra-Golgitransport It also remains possible that a single cell usesdifferent mechanisms of intra-Golgi transport depending onthe amount and type of cargo or its physiological statusMeanwhile cisternal maturation in combination with tubulartransient connections is a very attractive and intuitive modelthat seems to fit most experimental data

Acknowledgments

The work in this paper was supported by Grants fromthe Ministerio de Ciencia e Innovacion (Spain) ConsoliderCOAT (CSD2009-00016) and Fundacion Seneca de la Comu-nidadAutonoma de la Region deMurcia (04542GERM06)

References

[1] G Palade ldquoIntracellular aspects of the process of protein syn-thesisrdquo Science vol 189 no 4200 pp 347ndash358 1975

[2] W Nickel and C Rabouille ldquoMechanisms of regulated uncon-ventional protein secretionrdquo Nature Reviews Molecular CellBiology vol 10 no 2 pp 148ndash155 2009

[3] M G Farquhar and G E Palade ldquoThe Golgi apparatus (com-plex) (1954ndash1981) from artifact to center stagerdquo Journal of CellBiology vol 91 no 3 pp 77sndash103s 1981

[4] M G Farquhar and G E Palade ldquoThe Golgi apparatus 100years of progress and controversyrdquo Trends in Cell Biology vol8 no 1 pp 2ndash10 1998

10 ISRN Cell Biology

[5] C Wilson R Venditti L R Rega A Colanzi G DrsquoAngeloandM A De ldquoThe Golgi apparatus an organelle with multiplecomplex functionsrdquo Biochemical Journal vol 433 no 1 pp 1ndash92011

[6] J Lippincott-Schwartz E Snapp and A Kemvorthy ldquoStudyingprotein dynamics in living cellsrdquoNature Reviews Molecular CellBiology vol 2 no 6 pp 444ndash456 2001

[7] G Perinetti T Muller A Spaar R Polishchuk A Luini andA Egner ldquoCorrelation of 4Pi and electron microscopy to studytransport through single golgi stacks in living cells with superresolutionrdquo Traffic vol 10 no 4 pp 379ndash391 2009

[8] J Lippincott-Schwartz ldquoEmerging in vivo analyses of cellfunction using fluorescence imagingrdquo Annual Review of Bio-chemistry vol 80 pp 327ndash332 2011

[9] A Gilchrist C E Au J Hiding et al ldquoQuantitative proteomicsanalysis of the secretory pathwayrdquo Cell vol 127 no 6 pp 1265ndash1281 2006

[10] J Gannon J J Bergeron and T Nilsson ldquoGolgi and relatedvesicle proteomics simplify to identifyrdquo Cold Spring HarborPerspectives in Biology vol 3 no 12 2011

[11] F Bard L Casano A Mallabiabarrena et al ldquoFunctionalgenomics reveals genes involved in protein secretion and Golgiorganizationrdquo Nature vol 439 pp 604ndash607 2006

[12] J W Slot and H J Geuze ldquoImmunoelectron microscopicexploration of theGolgi complexrdquo Journal ofHistochemistry andCytochemistry vol 31 no 8 pp 1049ndash1056 1983

[13] D ZeuschnerW J C Geerts E vanDonselaar et al ldquoImmuno-electron tomography of ER exit sites reveals the existence of freeCOPII-coated transport carriersrdquoNature Cell Biology vol 8 no4 pp 377ndash383 2006

[14] R S Polishchuk E V Polishchuk P Marra et al ldquoCorrelativelight-electron microscopy reveals the tubular-saccular ultra-structure of carriers operating between Golgi apparatus andplasma membranerdquo Journal of Cell Biology vol 148 no 1 pp45ndash58 2000

[15] B S Donohoe S Mogelsvang and L A Staehelin ldquoElectrontomography of ER Golgi and related membrane systemsrdquoMethods vol 39 no 2 pp 154ndash162 2006

[16] N K Gonatas A Stieber and J O Gonatas ldquoFragmentationof the Golgi apparatus in neurodegenerative diseases and celldeathrdquo Journal of the Neurological Sciences vol 246 no 1-2 pp21ndash30 2006

[17] M C Derby and P A Gleeson ldquoNew insights into membranetrafficking and protein sortingrdquo International Review of Cytol-ogy vol 261 pp 47ndash116 2007

[18] A A Mironov and M Pavelka The Golgi Apparatus State ofthe Art 110 Years after Camillo Golgirsquos Discovery Springer WienNewYork NY USA 2008

[19] E Papanikou and B S Glick ldquoThe yeast Golgi apparatusinsights and mysteriesrdquo FEBS Letters vol 583 no 23 pp 3746ndash3751 2009

[20] J H Wei and J Seemann ldquoMitotic division of the mammalianGolgi apparatusrdquo Seminars in Cell and Developmental Biologyvol 20 no 7 pp 810ndash816 2009

[21] M Anitei and B Hoflack ldquoExit from the trans-Golgi networkfrom molecules to mechanismsrdquo Current Opinion in Cell Biol-ogy vol 23 no 4 pp 443ndash451 2011

[22] J Klumperman ldquoArchitecture of the mammalian Golgirdquo ColdSpring Harbor Perspectives in Biology vol 3 no 7 Article IDa005181 2011

[23] YWang and J Seemann ldquoGolgi biogenesisrdquoCold Spring HarborPerspectives in Biology vol 3 no 10 Article ID a005330 2011

[24] K W Moremen M Tiemeyer and A V Nairn ldquoVertebrateprotein glycosylation diversity synthesis and functionrdquoNatureReviews Molecular Cell Biology vol 13 pp 448ndash462 2012

[25] A J Dalton and M D Felix ldquoA comparative study of the Golgicomplexrdquo The Journal of Biophysical and Biochemical Cytologyvol 2 no 4 pp 79ndash84 1956

[26] A Rambourg Y Clermont and A Marraud ldquoThree dimen-sional structure of the osmium impregnated Golgi apparatus asseen in the high voltage electronmicroscoperdquoAmerican Journalof Anatomy vol 140 no 1 pp 27ndash46 1974

[27] A Rambourg Y Clermont and L Hermo ldquoThree-dimensionalarchitecture of the Golgi apparatus in Sertoli cells of the ratrdquoAmerican Journal of Anatomy vol 154 no 4 pp 455ndash476 1979

[28] M S Ladinsky D NMastronarde J RMcIntosh K E Howelland L A Staehelin ldquoGolgi structure in three dimensionsfunctional insights from the normal rat kidney cellrdquo Journal ofCell Biology vol 144 no 6 pp 1135ndash1149 1999

[29] R S Taylor S M Jones R H Dahl M H Nordeen andK E Howell ldquoCharacterization of the Golgi complex clearedof proteins in transit and examination of calcium uptakeactivitiesrdquo Molecular Biology of the Cell vol 8 no 10 pp 1911ndash1931 1997

[30] MMWuM Grabe S Adams R Y Tsien H P HMoore andT E Machen ldquoMechanisms of pH regulation in the regulatedsecretory pathwayrdquo Journal of Biological Chemistry vol 276 no35 pp 33027ndash33035 2001

[31] J HWei and J Seemann ldquoUnraveling theGolgi ribbonrdquoTrafficvol 11 no 11 pp 1391ndash1400 2010

[32] A A Mironov and G V Beznoussenko ldquoMolecular mecha-nisms responsible for formation of Golgi ribbonrdquoHistology andHistopathology vol 26 no 1 pp 117ndash133 2011

[33] B Storrie JWhite S Rottger E H K Stelzer T Suganuma andT Nilsson ldquoRecycling of Golgi-resident glycosyltransferasesthrough the ER reveals a novel pathway and provides anexplanation for nocodazole-induced Golgi scatteringrdquo Journalof Cell Biology vol 143 no 6 pp 1505ndash1521 1998

[34] J Fan Z Hu L Zeng et al ldquoGolgi apparatus and neurode-generative diseasesrdquo International Journal of DevelopmentalNeuroscience vol 26 no 6 pp 523ndash534 2008

[35] Y Fujita EOhamaMTakatama S Al-Sarraj andKOkamotoldquoFragmentation of Golgi apparatus of nigral neurons with120572-synuclein-positive inclusions in patients with Parkinsonrsquosdiseaserdquo Acta Neuropathologica vol 112 no 3 pp 261ndash2652006

[36] G Thorne-Tjomsland M Dumontier and J C Jamiesonldquo3D topography of noncompact zone Golgi tubules in ratspermatids a computer-assisted serial section reconstructionstudyrdquoThe Anatomical Record vol 250 pp 381ndash396 1998

[37] A S Opat C Van Vliet and P A Gleeson ldquoTrafficking andlocalisation of residentGolgi glycosylation enzymesrdquoBiochimievol 83 no 8 pp 763ndash773 2001

[38] M G Farquhar and H P Hauri ldquoProtein sorting and vesiculartraffic in the Golgi apparatusrdquo inTheGolgi Apparatus E Bergerand J Roth Eds pp 63ndash128 Birkhauser Basel Switzerland1997

[39] G van Meer ldquoLipids of the Golgi membranerdquo Trends in CellBiology vol 8 no 1 pp 29ndash33 1998

[40] J C M Holthuis T Pomorski R J Raggers H Sprong andG Van Meer ldquoThe organizing potential of sphingolipids in

ISRN Cell Biology 11

intracellular membrane transportrdquo Physiological Reviews vol81 no 4 pp 1689ndash1723 2001

[41] D K Banfield ldquoMechanisms of protein retention in the GolgirdquoCold Spring Harbor Perspectives in Biology vol 3 Article IDa005264 2011

[42] D J Gill J Chia J Senewiratne and F Bard ldquoRegulation ofO-glycosylation through Golgi-to-ER relocation of initiationenzymesrdquo Journal of Cell Biology vol 189 no 5 pp 843ndash8582010

[43] A Sesso F Paulo de Faria E S M Iwamura and H Correa ldquoAthree-dimensional reconstruction study of the rough ER-Golgiinterface in serial thin sections of the pancreatic acinar cell ofthe ratrdquo Journal of Cell Science vol 107 no 3 pp 517ndash528 1994

[44] Y Clermont A Rambourg and L Hermo ldquoConnectionsbetween the various elements of the cis- and mid-compart-ments of the Golgi apparatus of early rat spermatidsrdquo Anatomi-cal Record vol 240 no 4 pp 469ndash480 1994

[45] A Rambourg and Y Clermont ldquoThree-dimensional structureof the Golgi apparatus in mammalian cellsrdquo in The GolgiApparatus E G Berger and J Roth Eds pp 37ndash61 BirkhauserBasel Switzerland 1997

[46] G Vivero-Salmeron J Ballesta and J A Martınez-MenarguezldquoHeterotypic tubular connections at the endoplasmic reticu-lum-Golgi complex interfacerdquo Histochemistry and Cell Biologyvol 130 pp 709ndash717 2008

[47] C vanVliet E CThomas AMerino-Trigo R D Teasdale andP A Gleeson ldquoIntracellular sorting and transport of proteinsrdquoProgress in Biophysics and Molecular Biology vol 83 no 1 pp1ndash45 2003

[48] G Griffiths S Pfeiffer K Simons and K Matlin ldquoExit of newlysynthesized membrane proteins from the trans cisterna of theGolgi complex to the plasmamembranerdquo Journal of Cell Biologyvol 101 no 3 pp 949ndash964 1985

[49] G Griffiths S D Fuller R BackMHollinshead S Pfeiffer andK Simons ldquoThe dynamic nature of the Golgi complexrdquo Journalof Cell Biology vol 108 no 2 pp 277ndash297 1989

[50] H J Geuze and D J Morre ldquoTrans-Golgi reticulumrdquo Journal ofElectron Microscopy Technique vol 17 no 1 pp 24ndash34 1991

[51] Y Clermont A Rambourg and L Hermo ldquoTrans-Golgi net-work (TGN) of different cell types three-dimensional structuralcharacteristics and variabilityrdquo Anatomical Record vol 242 no3 pp 289ndash301 1995

[52] R S Polishchuk andA AMironov ldquoStructural aspects of Golgifunctionrdquo Cellular andMolecular Life Sciences vol 61 no 2 pp146ndash158 2004

[53] P A Gleeson J G Lock M R Luke and J L Stow ldquoDomainsof the TGN coats tethers and G proteinsrdquo Traffic vol 5 no 5pp 315ndash326 2004

[54] F Bard and V Malhotra ldquoThe formation of TGN-to-plasma-membrane transport carriersrdquo Annual Review of Cell andDevelopmental Biology vol 22 pp 439ndash455 2006

[55] R D Klausner J G Donaldson and J Lippincott-SchwartzldquoBrefeldin A insights into the control of membrane traffic andorganelle structurerdquo Journal of Cell Biology vol 116 no 5 pp1071ndash1080 1992

[56] J Llopis J M McCaffery A Miyawaki M G Farquhar andR Y Tsien ldquoMeasurement of cytosolic mitochondrial andGolgi pH in single living cells with green fluorescent proteinsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 12 pp 6803ndash6808 1998

[57] H HMollenhauer andD J Morre ldquoThe tubular network of theGolgi apparatusrdquo Histochemistry and Cell Biology vol 109 no5-6 pp 533ndash543 1998

[58] L Orci A Perrelet and J E Rothman ldquoVesicles on stringsMorphological evidence for processive transport within theGolgi stackrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 95 no 5 pp 2279ndash2283 1998

[59] Y Xiang and Y Wang ldquoNew components of the Golgi matrixrdquoCell and Tissue Research vol 344 no 3 pp 365ndash379 2011

[60] N Nakamura C Rabouille R Watson et al ldquoCharacterizationof a cis-Golgi matrix protein GM130rdquo Journal of Cell Biologyvol 131 no 6 pp 1715ndash1726 1995

[61] P Slusarewicz T Nilsson N Hui R Watson and G WarrenldquoIsolation of amatrix that bindsmedial Golgi enzymesrdquo Journalof Cell Biology vol 124 no 4 pp 405ndash413 1994

[62] G Egea and R M Rios ldquoThe role of the cytoskeleton in thestructure and function of the Golgi apparatusrdquo in The GolgiApparatus A A Mironov and M Pavelka Eds pp 270ndash300Springer NewYork NY USA 2008

[63] M Lowe ldquoStructural organization of the Golgi apparatusrdquoCurrent Opinion in Cell Biology vol 23 no 1 pp 85ndash93 2011

[64] R M Rios and M Bornens ldquoThe Golgi apparatus at the cellcentrerdquoCurrent Opinion in Cell Biology vol 15 pp 60ndash66 2003

[65] S Yadav and A D Linstedt ldquoGolgi positioningrdquo Cold SpringHarbor Perspectives in Biology vol 3 pp 1ndash17 2011

[66] J K Burkhardt ldquoThe role of microtubule-based motor proteinsin maintaining the structure and function of the Golgi com-plexrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp 113ndash126 1998

[67] K Chabin-Brion J Marceiller F Perez et al ldquoThe Golgi com-plex is a microtubule-organizing organellerdquo Molecular Biologyof the Cell vol 12 no 7 pp 2047ndash2060 2001

[68] S Rivero J Cardenas M Bornens and R M Rios ldquoMicro-tubule nucleation at the cis-side of the golgi apparatus requiresAKAP450 and GM130rdquo The EMBO Journal vol 28 no 8 pp1016ndash1028 2009

[69] A Efimov A Kharitonov N Efimova et al ldquoAsymmetricCLASP-dependent nucleation of noncentrosomal microtubulesat the trans-Golgi Networkrdquo Developmental Cell vol 12 no 6pp 917ndash930 2007

[70] P M Miller A W Folkmann A R R Maia N EfimovaA Efimov and I Kaverina ldquoGolgi-derived CLASP-dependentmicrotubules control Golgi organization and polarized traffick-ing in motile cellsrdquo Nature Cell Biology vol 11 no 9 pp 1069ndash1080 2009

[71] F Valderrama A Luna T Babia et al ldquoThe Golgi-associatedCOPI-coated buds and vesicles contain 120573120574-actinrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 97 no 4 pp 1560ndash1565 2000

[72] G Egea F Lazaro-Dieguez and M Vilella ldquoActin dynamics atthe Golgi complex inmammalian cellsrdquoCurrent Opinion in CellBiology vol 18 pp 168ndash178 2006

[73] F Lazaro-Dieguez C Colonna M Cortegano M Calvo S EMartınez and G Egea ldquoVariable actin dynamics requirementfor the exit of different cargo from the trans-Golgi networkrdquoFEBS Letters vol 581 no 20 pp 3875ndash3881 2007

[74] F Valderrama J M Duran T Babia H Barth J Renau-Piqueras and G Egea ldquoActin microfilaments facilitate theretrogade transport from the Golgi complex to the endoplasmicreticulum in mammalian cellsrdquo Traffic vol 2 no 10 pp 717ndash726 2001

12 ISRN Cell Biology

[75] A Disanza and G Scita ldquoCytoskeletal regulation coordinatingactin and microtubule dynamics in membrane traffickingrdquoCurrent Biology vol 18 no 18 pp R873ndashR875 2008

[76] K G Campellone N J Webb E A Znameroski and M DWelch ldquoWHAMM is an Arp23 complex activator that bindsmicrotubules and functions in ER to golgi transportrdquo Cell vol134 no 1 pp 148ndash161 2008

[77] Q T Shen P P Hsiue C V Sindelar M D Welch KG Campellone and H W Wang ldquoStructural insights intoWHAMM-mediated cytoskeletal coordination during mem-brane remodelingrdquoThe Journal of Cell Biology vol 199 pp 111ndash124 2012

[78] T F Roth and K R Porter ldquoYolk protein uptake in the oocyteof the mosquito Aedes aegypti Lrdquo The Journal of Cell Biologyvol 20 pp 313ndash332 1964

[79] B M F Pearse ldquoClathrin a unique protein associated withintracellular transfer of membrane by coated vesiclesrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 73 no 4 pp 1255ndash1259 1976

[80] A Oprins R Duden T E Kreis H J Geuze and J W Slotldquo120573-COP localizes mainly to the cis-Golgi side in exocrinepancreasrdquo Journal of Cell Biology vol 121 no 1 pp 49ndash60 1993

[81] B M F Pearse and M S Robinson ldquoClathrin adaptors andsortingrdquo Annual Review of Cell Biology vol 6 pp 151ndash171 1990

[82] T Braulke and J S Bonifacino ldquoSorting of lysosomal proteinsrdquoBiochimica et BiophysicaActa vol 1793 no 4 pp 605ndash614 2009

[83] T Kirchhausen ldquoClathrinrdquo Annual Review of Biochemistry vol69 pp 699ndash727 2000

[84] E Rodriguez-Boulan and A Musch ldquoProtein sorting in theGolgi complex shifting paradigmsrdquo Biochimica et BiophysicaActa vol 1744 no 3 pp 455ndash464 2005

[85] M A McNiven H Cao K R Pitts and Y Yoon ldquoThe dynaminfamily of mechanoenzymes pinching in new placesrdquo Trends inBiochemical Sciences vol 25 no 3 pp 115ndash120 2000

[86] E Eisenberg and L E Greene ldquoMultiple roles of auxilin andHsc70 in clathrin-mediated endocytosisrdquo Traffic vol 8 no 6pp 640ndash646 2007

[87] C Barlowe L Orci T Yeung et al ldquoCOPII a membrane coatformed by sec proteins that drive vesicle budding from theendoplasmic reticulumrdquo Cell vol 77 no 6 pp 895ndash907 1994

[88] L C Bickford E Mossessova and J Goldberg ldquoA structuralview of the COPII vesicle coatrdquo Current Opinion in StructuralBiology vol 14 no 2 pp 147ndash153 2004

[89] D Jensen and R Schekman ldquoCOPII-mediated vesicle forma-tion at a glancerdquo Journal of Cell Science vol 124 no 1 pp 1ndash42011

[90] T Kirchhausen ldquoMaking COPII coatsrdquo Cell vol 129 no 7 pp1251ndash1252 2007

[91] C Barlowe ldquoCOPII and selective export from the endoplasmicreticulumrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp67ndash76 1998

[92] J A Martınez-Menarguez H J Geuze J W Slot and JKlumperman ldquoVesicular tubular clusters between the ER andGolgi mediate concentration of soluble secretory proteins byexclusion fromCOPI-coated vesiclesrdquoCell vol 98 no 1 pp 81ndash90 1999

[93] K Saito M Chen F Bard et al ldquoTANGO1 facilitates cargoloading at endoplasmic reticulum exit sitesrdquo Cell vol 136 no5 pp 891ndash902 2009

[94] L Jin K B Pahuja K E Wickliffe et al ldquoUbiquitin-dependentregulation of COPII coat size and functionrdquo Nature vol 482pp 495ndash500 2012

[95] H P Hauri and A Schweizer ldquoThe endoplasmic reticulum-Golgi intermediate compartmentrdquo Current Opinion in CellBiology vol 4 no 4 pp 600ndash608 1992

[96] S I Bannykh T Rowe and W E Balch ldquoThe organizationof endoplasmic reticulum export complexesrdquo Journal of CellBiology vol 135 no 1 pp 19ndash35 1996

[97] J Saraste and E Kuismanen ldquoPre- and post-Golgi vacuolesoperate in the transport of Semliki Forest virus membraneglycoproteins to the cell surfacerdquo Cell vol 38 no 2 pp 535ndash549 1984

[98] A Schweizer J A M Fransen K Matter T E Kreis L GinselandH PHauri ldquoIdentification of an intermediate compartmentinvolved in protein transport from endoplasmic reticulum toGolgi apparatusrdquo European Journal of Cell Biology vol 53 no 2pp 185ndash196 1990

[99] H Ben-Takaya K Miura R Pepperkok and H P Hauri ldquoLiveimaging of bidirectional traffic from the ERGICrdquo Journal of CellScience vol 118 no 2 pp 357ndash367 2005

[100] Y C Zhang Y Zhou C Z Yang and D S Xiong ldquoA reviewof ERGIC-53 its structure functions regulation and relationswith diseasesrdquo Histology and Histopathology vol 24 no 9 pp1193ndash1204 2009

[101] J F Presley N B Cole T A Schroer K Hirschberg K JM Zaal and J Lippincott-Schwartz ldquoER-to-Golgi transportvisualized in living cellsrdquo Nature vol 389 no 6646 pp 81ndash851997

[102] J A Martınez-Menarguez H J Geuze and J Ballesta ldquoIdenti-fication of two types of beta-COP vesicles in the Golgi complexof rat spermatidsrdquo European Journal of Cell Biology vol 71 pp137ndash143 1996

[103] J Lippincott-Schwartz J G Donaldson A Schweizer et alldquoMicrotubule-dependent retrograde transport of proteins intothe ER in the presence of brefeldin A suggests an ER recyclingpathwayrdquo Cell vol 60 no 5 pp 821ndash836 1990

[104] A Girod B Storrie J C Simpson et al ldquoEvidence for a COP-I-independent transport route from the Golgi complex to theendoplasmic reticulumrdquo Nature Cell Biology vol 1 no 7 pp423ndash430 1999

[105] V Popoff F Adolf B Brugger and F Wieland ldquoCOPI buddingwithin the Golgi stackrdquo Cold Spring Harbor Perspectives inBiology vol 3 Article ID a005231 2011

[106] J Moelleken J Malsam M J Betts et al ldquoDifferential localiza-tion of coatomer complex isoforms within the Golgi apparatusrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 104 no 11 pp 4425ndash4430 2007

[107] L Orci B S Glick and J E Rothman ldquoA new type of coatedvesicular carrier that appears not to contain clathrin its possiblerole in protein transport within theGolgi stackrdquoCell vol 46 no2 pp 171ndash184 1986

[108] V Malhotra T Serafini L Orci J C Shepherd and J ERothman ldquoPurification of a novel class of coated vesiclesmediating biosynthetic protein transport through the Golgistackrdquo Cell vol 58 no 2 pp 329ndash336 1989

[109] M G Waters T Serafini and J E Rothman ldquolsquoCoatomerrsquo acytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesiclesrdquo Nature vol 349 no 6306 pp248ndash251 1991

[110] T Serafini L Orci M Amherdt M Brunner R A Kahn andJ E Rothman ldquoADP-ribosylation factor is a subunit of the coatof Golgi-derived COP-coated vesicles a novel role for a GTP-binding proteinrdquo Cell vol 67 no 2 pp 239ndash253 1991

ISRN Cell Biology 13

[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

[112] K Kawamoto Y Yoshida H Tamaki et al ldquoGBF1 a guaninenucleotide exchange factor for ADP-ribosylation factors islocalized to the cis-Golgi and involved inmembrane associationof the COPI coatrdquo Traffic vol 3 no 7 pp 483ndash495 2002

[113] R Garcıa-Mata T Szul C Alvarez and E Sztul ldquoADP-ribosylation factorCOPI-dependent events at the endoplas-mic reticulum-Golgi interface are regulated by the guaninenucleotide exchange factor GBF1rdquoMolecular Biology of the Cellvol 14 no 6 pp 2250ndash2261 2003

[114] H Inoue and P A Randazzo ldquoArf GAPs and their interactingproteinsrdquo Traffic vol 8 no 11 pp 1465ndash1475 2007

[115] G Tanigawa L Orci M Amherdt M Ravazzola J B Helmsand J E Rothman ldquoHydrolysis of bound GTP by ARF proteintriggers uncoating of Golgi- derived COP-coated vesiclesrdquoJournal of Cell Biology vol 123 no 6 pp 1365ndash1371 1993

[116] Y Shiba and P A Randazzo ldquoArfGAP1 function in COPImediated membrane traffic currently debated models andcomparison to other coat-binding ArfGAPsrdquo Histology andHistopathology vol 27 pp 1143ndash1153 2012

[117] J Bigay P Gounon S Roblneau and B Antonny ldquoLipidpacking sensed by ArfGAP1 couples COPI coat disassembly tomembrane bilayer curvaturerdquo Nature vol 426 no 6966 pp563ndash566 2003

[118] W Nickel J Malsam K Gorgas et al ldquoUptake by COPI-coatedvesicles of both anterograde and retrograde cargo is inhibitedby GTP120574S in vitrordquo Journal of Cell Science vol 111 no 20 pp3081ndash3090 1998

[119] R Beck M Rawet F T Wieland and D Cassel ldquoThe COPIsystemmolecularmechanisms and functionrdquo FEBS Letters vol583 pp 2701ndash2709 2009

[120] F Letourneur E C Gaynor S Hennecke et al ldquoCoatomeris essential for retrieval of dilysine-tagged proteins to theendoplasmic reticulumrdquo Cell vol 79 no 7 pp 1199ndash1207 1994

[121] R Schindler C Itin M Zerial F Lottspeich and H P HaurildquoERGIC-53 a membrane protein of the ER-Golgi intermediatecompartment carries an ER retention motifrdquo European Journalof Cell Biology vol 61 no 1 pp 1ndash9 1993

[122] L P Jackson M Lewis H M Kent et al ldquoMolecular basis forrecognition of dilysine trafficking motifs by COPIrdquo Develop-mental Cell vol 23 pp 1ndash8 2012

[123] W Nickel K Sohn C Bunning and F T Wieland ldquop23 Amajor COPI-vesicle membrane protein constitutively cyclesthrough the early secretory pathwayrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 94 no21 pp 11393ndash11398 1997

[124] J C Semenza K G Hardwick N Dean and H R BPelham ldquoERD2 a yeast gene required for the receptor-mediatedretrieval of luminal ER proteins from the secretory pathwayrdquoCell vol 61 no 7 pp 1349ndash1357 1990

[125] I Majoul M Straub S W Hell R Duden and H D SolingldquoKDEL-cargo regulates interactions between proteins involvedin COPI vesicle traffic measurements in living cells usingFRETrdquo Developmental Cell vol 1 no 1 pp 139ndash153 2001

[126] B S Glick ldquoOrganization of the Golgi apparatusrdquo CurrentOpinion in Cell Biology vol 12 no 4 pp 450ndash456 2000

[127] R Blum D J Stephens and I Schulz ldquoLumenal targeted GFPused as a marker of soluble cargo visualises rapid ERGIC toGolgi traffic by a tubulo-vesicular networkrdquo Journal of CellScience vol 113 no 18 pp 3151ndash3159 2000

[128] J C Simpson T Nilsson and R Pepperkok ldquoBiogenesis oftubular ER-to-golgi transport intermediatesrdquoMolecular Biologyof the Cell vol 17 no 2 pp 723ndash737 2006

[129] K Hirschberg C M Miller J Ellenberg et al ldquoKinetic analysisof secretory protein traffic and characterization of Golgi toplasma membrane transport intermediates in living cellsrdquoJournal of Cell Biology vol 143 no 6 pp 1485ndash1503 1998

[130] D Toomre P Keller JWhite J C Olivo and K Simons ldquoDual-color visualization of trans-Golgi network to plasmamembranetraffic alongmicrotubules in living cellsrdquo Journal of Cell Sciencevol 112 no 1 pp 21ndash33 1999

[131] L Hermo A Rambourg and Y Clermont ldquoThree-dimensionalarchitecture of the cortical region of the Golgi apparatus in ratspermatidsrdquo American Journal of Anatomy vol 157 no 4 pp357ndash373 1980

[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

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Microbiology

4 ISRN Cell Biology

present in mannose-6-phosphate receptors and contribute tothe sorting of these receptors which their cargo hydrolysesinto clathrin-coated vesicles [82] AP1 AP3 and AP4 (in thiscase independently of clathrin) are involved in the sortingof lysosomal membrane proteins at the TGN In polarizedcells AP1 AP3 and AP4 are involved in the sorting of baso-lateral membrane proteins but probably through a clathrin-independent mechanism [84] The binding of cargo andadaptor recruits clathrin which provides the scaffold for theinvagination of the membrane forming a coated pit Fissionof the vesicle requires the activity of the GTPase dynamin[85] whereas vesicle uncoating depends on recruitment ofthe chaperone Hsc70 by the nerve-specific auxilin or theubiquitous GAK [86]

COPII- and COPI-coated vesicles are morphologicallyvery similar They are 50ndash60 nm in diameter with a 10 nm-thick coat However their composition location and role intransport differ The COPII coat is formed of five proteinsSec23 Sec24 Sec13 Sec 31 and the GTPase Sar1 [87 88]These proteins are soluble in the cytosol but associated toform coated buds at the ER Sar1 is the first componentrecruited in ER membranes This binding depends on theactivation of this GTPase by Sec12 a guanine nucleotideexchange factor (GEF) present in ER membranes [89] Sar1recruits the Sec23Sec24 heterodimer and then the Sec13Sec31 complex [90] During this process some proteins areselectively recruited in COPII vesicles [91] whereas othersenter unspecifically a process known as bulk flow [92] Thesize of the COPII vesicles can be adapted to a bulky cargoTANGO 1 is an adaptor protein that helps collagen VII toenter into vesicles [93] Recently it has been shown that ubiq-uitination of Sec31 regulated the formation of large COPIIvesicles [94] The role of COPII in ER-to-Golgi transport iswell established In specific places of the ER the ER exit sitesthis coat complex drives the formation of free coated vesiclescontaining cargoThese are quickly uncoated and fuse to eachother to form the so-called endoplasmic reticulum-Golgiintermediate compartment (ERGIC) or vesicular-tubularaggregates (VTCs) [95] This compartment is formed oftubulovesicular elements located close to the GC and dis-tributed throughout the cell and is associated to ER exit sites[96] This compartment was initially identified because thecargo accumulated in these elements when cells are culturedat low temperature (15∘C) [97 98] At the ERGIC the COPIcoat mediates the recycling of proteins back to the ER whileanterograde cargo is separated and concentrated It is notclear whether the ERGIC is a stable and static compartmentor conversely whether it works as a carrier [99] The factthat the proteins associated with this compartment are notresident but cycling between the ER and Golgi argues againstthe idea that it is a stable compartment This is the casewith ERGIC-53 a type I transmembrane protein of the lectinfamily which is the prototypical marker of this compartment[100] Anyway ERGIC elements or ERGIC-derived carriersmove to theGolgi area along themicrotubule track and therethey may fuse to each other to form the CGN or converselyfuse with a preexisting cisterna [101]

COPI-coated vesicles are found in peripheral and cen-tral ERGIC elements cis and lateral Golgi sides [80] and

occasionally at the trans-Golgi sideTGN [102] COPI-coatedbuds are observed at the lateral rims of cisternae decreasingin number in a cis to trans direction [28] COPI and clathrin-coated areas have been observed in immature secretorygranules [92] The function of the COPI coat in the Golgi-to-ER retrograde transport of soluble and membrane pro-teins has been convincingly demonstrated [103] Howeverthere are retrograde routes to the ER independent of COPI[104] COPI has also been associated with the anterogradeand retrograde intra-Golgi transport of cargo and residentenzymes respectively although this role remains highly con-troversial (see below) COPI coats are also involved in Golgifragmentation duringmitosis Golgi positioning lipid home-ostasis and endocytic routes [105] It is possible that thereare several subpopulations of COPI vesicles with differentcompositions and locations each carrying out its specificfunctions [106] The discovery and characterization of COPIvesicles data from the early 1980s when transport intermedi-ates were analyzed in cell-free experiments incubatingGolgi-enriched membranes with cytosol and GTP120574S [107 108]COPI coats are formed of seven subunits (120572 120573 1205731015840 120574 120575 120576120577-COP) assembled in the cytosol where they form a complexnamed coatomer [109] and the small GTPase ARF1 [110]ARF1 cycles between GDP- and GTP-bound forms [111]GTP-bound ARF1 binds to membranes and recruits thecoatomer en bloc resulting in membrane deformation Likeall small GTPases the activity of ARF1 is regulated by guaninenucleotide exchange factors (GEPs) and GTPase-activatingprotein (GAP) GEF catalyzes the exchange ofGDPwithGTPGolgi-associated BFA-resistant protein (GBF1) is the majorGEF for ARF1 during COPI vesicle formation in the Golgimembranes and is the target of the drug brefeldin A [112 113]Brefeldin A blocks the ARF1-GEF complex inhibiting theformation of ARF1-GTP and triggering Golgi disassemblyARFGAP proteins stimulate the GTP hydrolysis of ARFwhich has low intrinsic GTPase activity [114] It has beenpostulated that this reaction triggers uncoating [115] butthis point is under discussion [116] The proteins BARS andendophilinB seem to be necessary for the fission of COPIvesicles Interestingly ARFs have a role in the recruitmentand activation of lipid-modifying enzymes In additionARFGAP1 the first identified GAP for ARF1 is a membranecurvature sensor [117] Cargo inclusion requires GTP hydrol-ysis [118] For cargo sorting coatomer recognizes dibasicsequences [105 119] Many transmembrane proteins trans-ported into COPI vesicles bear dilysine motifs at their C-terminus [120] including ERGIC-53 [121] The coatomersubunits 120572- and 1205731015840-COP bind this signal directly [122] Thep24 family of proteins (23-24 kD transmembrane proteins)are recruited by direct interaction of their cytoplasmic tailwhich contains phenylalanine- and dilysine-based signals tocoatomer [123] However not all cargo incorporated in COPIvesicles have this sorting signal and may require adaptorsOne example is the KDEL receptor a transmembrane proteinmostly present in the cis Golgi and ERGIC that works as anadaptor for soluble proteins It interacts with the coatomerthrough a dilysine motif in the cytosolic tail whereas theluminal part interacts with soluble proteins bearing a K-D-E-L sequence (HDEL in yeast) a sequence found in many

ISRN Cell Biology 5

ER-resident proteins [124 125] In this way soluble proteinsthat have escaped from the ER are retrieved Glycosylationenzymes may also require cargo adaptors [105]

4 Transport Carriers Tubules andHeterogenic Elements

For a long time it was assumed that membrane traffic ismediated by coated vesicles Although they play a key role inmany steps of the transport it is possible that coated vesiclesjust represent a fraction of the intermediate transport carriersoperating in the secretory pathway [126] Tubular elementson the other hand have been associated with all steps ofthe secretory pathway (Polishchuk and Mironov [52]) Thetransport of soluble [127] and transmembrane [99] cargofrom pre-Golgi elements to the Golgi is mediated by tubulesTubules are 20 of the elements operating at the ER-Golgiinterface [128] Post-Golgi carriers may also have a tubularform [129 130] In fact the TGN itself is often formed by anetwork of branching tubules

Tubules are also involved in intra-Golgi transport TheGC is associated to an extensive network of 30 nm-thicktubules connected to the lateral edges of the stacked cisternaeand may extend a considerable distance from the stacks [57]Golgi tubules were already observed in the first electronmicroscopical observations of this organelle [25] Early stud-ies showed tubular elements emerging from the Golgi stackand TGN connected to cisternae or oriented towards thecytoplasm [26 27] Hermo and coworkers [131] describedtubular connections between cisternae in the cis side of theGolgi apparatus of spermatids Despite this tubules werealmost forgotten in the field for decades probably due tothe difficulty of identifying them in bidimensional electronmicrographs (they only can be identified in longitudinalsections) This was exacerbated cisternal maturation modelbeing abandoned in favor of the vesicular transport modelResearch into these elements increased with the introductionof the drug brefeldin A in the study of the GC This druginduces extensive tubulation of this organelle Although thissystem is artificial it has been postulated that brefeldinA exaggerates the natural process of retrograde transportHowever in contrast with normal conditions this transportoccurs only after the dissociation of COPI coats from theGC The development of new methodologies such as time-lapse confocal microscopy or electron tomography hasreintroduced the idea that tubules are transport intermedi-ates Time-lapse analysis of living cells has shown tubulesemerging from the GC [132] containing GFP-tagged residentenzymes [133] or cargo [101 134] Electron tomography con-firms that these elements are commonly associated to theGC [28 135] In NRK cells there are tubules that emergefrom cis and trans cisternae suggesting that they are involvedin incoming and outgoing Golgi trafficking Tubules maygrow from all cisternae and may extend towards CGN andTGN Interestingly one single cisterna may contain tubulesoriented to both cis and trans faces [28] In cells stimulatedto increase the secretion rate tubular connections betweencisternae are evident [136 137] but these connections

disappear when cargo has left the GC Thus tubules mightreplace vesicles when there is an excess of cargo Tubules mayalso participate in the recycling of Golgi resident enzymesUnder low temperature (15∘C) conditions many tubulesemerge from theGC ofHeLa cellsThese tubules are enrichedin Golgi-resident enzymes and a specific set of SNAREand Rab proteins associated with intra-Golgi transport andcontain neither retrograde nor anterograde cargo [138 139]This type of tubule can also be observed under physiologicalconditions and they are good candidates for being consideredtransport intermediates at the Golgi level Several types oftubules with different functions may well exist

The molecular machinery involved in the formation ofGolgi tubules is just beginning to be known Based onbrefeldin A experiments tubular formation at the GC hasbeen related with the loss of COPI coats [140 141] GTP-bound ARF1 is able to induce Golgi tubules by insertion ofthe amino-terminal amphipathic helix [142] Microtubule-associated motor proteins are sufficient to induce tubulesfrom Golgi membranes [143] Some lipidic species such asphosphatidic acid diacylglycerol and lysophosphatidic acidfavor the curvature of membranes Thus enzymes associatedwith lipid metabolism play a key role in tubular formationLysophosphatidic acid generated by the enzyme phospho-lipase A2 has been involved in the retrograde transportmediated by tubules [144 145] Agonist and antagonist of thisenzyme increase or inhibit tubular formation respectivelyThis enzyme is involved in the formation of tubular continu-ities between cisternae [146] and tubular transport interme-diates at the TGN [147] The formation of transport carriersat the TGN is also diacylglycerol dependent This lipid isnecessary to recruit protein kinaseD a regulator of the fissionof transport carriers [54 148] Diacylglycerol has also beeninvolved in Golgi-to-ER retrograde transport mediated bytubules [149] Phosphatidic acid has been involved in intra-Golgi transport [150] Interestingly two lipid-modifyingenzymes lysophosphatidic acid acyltransferase-120574 and phos-pholipase A2-120572 which promote or inhibit COPI fissionrespectively work together regulating the morphology ofGolgi carriers [151] On the other hand the morphology ofpre-Golgi tubules depends on the cargo [128] COPI coatsmicrotubules and associated motor proteins [152] and alsothe activity of ARF and phospholipase A2 [153]Thus similarmachineries may be operating at different levels of the secre-tory pathway Interestingly live cell imaging shows that pre-Golgi elements may change their morphology very quicklyfrom vesicular to tubular form and vice versa [152]

Apart from the tubules other transport intermediates ofheterogeneous morphology have been described Polishchukand coworkers [154] described the formation of large tubulo-saccular elements involved in the microtubule-dependenttransport from the TGN to the plasma membrane The samegroup has described heterogenic membranes involved in ER-to-Golgi transport [155] Very large pleiomorphicmembrane-bound elements have also been associated with transportin the early secretory pathway [156] It seems that thereare different classes of transport carriers depending of theamount or type of cargo

6 ISRN Cell Biology

5 Molecular Machinery

In recent decades a huge amount of information has beenaccumulated about the molecular machinery involved inthe regulation of the intercompartmental transport in thesecretory pathway Most data refer to vesicles as transportcarriers but it can be assumed that the same or similar mech-anisms operate for other carriers If the formation of vesiclesand the selection of cargo depends on the coatmachinery thespecific targeting and fusion of the carriers with the targetmembranes depends on tethering factors Rab and SNAREproteins and other accessory proteins [157] In a simplemodel the rabs on incoming vesicles recruit tethering factorswhich permits SNARE complex formation

SNAREs (soluble N-ethylmaleimide-sensitive factorattachment proteins receptors) proteins are involved indocking and the specific fusion of transport intermediateswith the targetmembranes [157ndash159]The SNAREs associatedwith vesicles (or other transport intermediates) and targetmembranes have been named v- and t-SNARE respectivelyThis terminology however is not useful for describinghomotypic fusion events Structurally SNAREs have beendivided into R- and Q-SNAREs according to the centralresidue (RGln or QArg resp) of the SNARE domain aconserved region of 60ndash70 residues found in all members ofthis family Although there are some exceptions v-SNAREand t-SNARE are R-SNARE and Q-SNARE respectivelyInteraction between one v-SNARE and twothree t-SNAREinduces the formation of the trans-SNARE complex whichcatalyzes the fusion of the membranes SNARE proteins aresufficient to drive membrane fusion so that they are con-sidered the minimal membrane fusion machinery Afterfusion a cis-SNARE complex is formed in the target mem-branes This complex is later disassembled by the action ofthe cytosolic proteins 120572-SNAP (soluble N-ethylmaleimide-sensitive factor attachment protein) and the ATPase NSF(N-ethylmaleimide-sensitive factor) Now v-SNARE can betransported back to the donor compartment to be reusedSeveral SNARE complexes working at the secretoryendo-cytic pathway have been identified In mammalian cellstwo SNARE complexes have been implicated in intra-Golgitransport [160] A complex is formed of v-SNARE GS15 andthe t-SNAREs syntaxin5 GOS28 and Ykt6 is involved inCOPI-dependent intra-Golgi transport The second complexis formed of syntaxin 5 membrin (GS27) ERS24Sec22 andrBet1 the last one acting as v-SNARE This second complexhas been also involved in the fusion ER-derived elementswith the cis-Golgi and possible intra-Golgi transport Thedistribution of these SNAREs across the Golgi stack isdifferent Thus in general the components of the first com-plex increase in concentration toward the trans side whereasthe components of the second complex decrease [161]supporting the idea that these complexes mediate transportevents in opposite directions Syntaxin 5 which is present inboth complexes is distributed homogeneously through thestack SNARE complex assembly is regulated by SM (Sec1Munc18) proteins a family of cytosolic proteins Sly1 I isthe only member of this family operating at the ER-Golgiarea where it interacts with syntaxin 5 and syntaxin 18 at

the Golgi and ER respectively and controls anterograde andretrograde transport between these compartments [162]

Rab proteins are a family of small GTPases regulatingmembrane transport by recruiting effector proteins [159 163]They are localized at the cytoplasmic face of secretory andendocytic compartments and carriers and they have beenimplicated in vesicle budding uncoating mobility and trans-port Rab switches between an active form (GTP-bound) anda cytosolic inactive form (GDP-bound) Rab proteins in theGTP-bound form are reversibly associated with membranesby geranylgeranyl groups recruiting a variety of effectorsincluding sorting adaptors tethering factors kinases phos-phatases and motor proteins [163] The replacement of GDPby GTP is facilitated by guanine nucleotide exchange factors(GEFs) and their low intrinsic GTPase activity is enhancedby GTPase-activating proteins (GAP) Further regulation ofthe GTPGDP state and membrane association is providedby GDP dissociation inhibitor (GDI) and GDI displacementfactors (GDFs) Rab protein is a large family includingmore than 60 members in humans and 11 in yeast whichare specifically associated with distinct compartments andtransport events [163] Thus Rab proteins have also beenassociated with the control of membrane identity by control-ling local levels of phosphoinositides which concomitantlymay recruit specific proteins to certain compartments [164]The association of Rab proteins with specific membranes isguided by Rab escort protein (REP) which presents newlysynthesized Rab to geranylgeranyl transferase before target-ing the membranes The Golgi-associated Rab family playinga key role in Golgi maintenance and functioning includesRab1 Rab2 Rab6 Rab33B Rab18 and Rab43 [165] Rab1 andRab2 are involved in ER-to-Golgi transport Rab 1 is also veryimportant for Golgi ribbon maintenance Interestingly thelevels of expression or the distribution of this small GTPaseis affected in neurological disorders that show fragmentationof the Golgi ribbon [166] (Rendon et al [167]) Rab6 andmore specifically the Rab6AArsquo isoform is the most widelystudiedGolgi-associated Rab protein [168] It is important formaintaining Golgi structure and also for regulating transportin and out of the GC including a COPI-independent Golgi-to-ER transport [169] It is also associated with post-Golgicarriers where it recruits motor proteins [170 171] and alsoregulates the docking and fusion with the plasma membrane[172] At the Golgi stack it anchors the tethering factorsnecessary for attaching incoming vesicles The organizationof the Golgi ribbon the regulation of the number of cisternaein the stack and transport of coated vesicles is also associatedwith Rab6 and effectors [173] Rab33B is localized specificallyin the medial Golgi [174] where it is involved in Golgi-to-ER retrograde transport [175] Interestingly Rab6A recruitsspecific GEF that also interacts with Rab33B connecting theseRabs in a Rab cascade [176]Most probably Rab6 and Rab33Bwork together in the regulation of intra-Golgi and Golgi-to-ER transport [165] Less information is available about Rab43and Rab18 but they are also thought to be involved in ER-Golgi trafficking and Golgi organization

Tethering factors are a group of membrane-associatedproteins or multisubunit complexes that link transport vesi-cles with the targetmembranes to ensure correct docking and

ISRN Cell Biology 7

fusion They have recently been classified into three classesoligomeric complexes that work as Rab effectors and bindsSNARE oligomeric complexes that function as GEFs for Rabproteins and finally coiled-coil tethers [177] Proteins withextensive coiled-coil domains are long allowing long distancetethering These bridges not only facilitate the formation ofSNARE complexes but also may provide an initial specificityfor membrane fusionMembers of this family associated withthe Golgi are called golgins [178] In addition to tetheringthey have a role in Golgi stacking and form the Golgi matrixThis family includes p115 and GM130 the first of which isassociated with COPI and COPII vesicles the ERGIC andcis-Golgi membranes This protein is believed to be involvedin tethering of COPII vesicles to ERGIC membranes and thetransport events from these elements to the cis-Golgi It is alsopossible that it participates in transport between cisternaeThe recruitment of p115 to membranes is Rab1 dependentIt also interacts with ER-Golgi SNAREs COG subunits andother coiled-coil proteins such as GM130 and giantin Thesignificance of the last interaction is not clear GM130 isanother coiled-coil protein associated with the cis Golgi Itinteracts with many proteins including GRASP65 p115 Rab1Rab2 Rab33b and sintaxin5 P115 and GM130 are membersof the family of golgins which were first identified as Golgi-localized autoantigens using antibodies derived from thesera of patients with a variety of autoimmune disorders Asindicated above GM130 and p115 are also components ofthe Golgi matrix Apart from their role as tethers togetherwith other members of the golgin family such as GRASP65and giantin they are involved in maintaining the stackedmorphology of the cisterna and the Golgi ribbon [179]

Multisubunit complexes associated with the Golgiinclude Dsl1 COG and TRAPPIII [177] Dsl1 is a three-unitcomplex involved in Golgi-to-ER transport where it acts astethering COPI vesicles It interacts and stabilizes an SNAREcomplex at the ER The conserved oligomeric Golgi (COG)complex formed of 8 subunits (Cog1ndash8) found at the cis- andmedial Golgi cisternae is believed to be involved in transportto the Golgi and intra-Golgi recycling of Golgi resident pro-teins [180] Components of this tethering factor interactwith COPI components SNARE proteins (syntaxin 5) andcoiled-coil tether (p115) and are the effectors of several Rabproteins (Rab1 Rab6) Transport protein particle (TRAPP) isanother multisubunit complex that works as tethering factor[181] Two complexes have been identified TRAPP I andTRAPPII which are involved in entry and exit from theGC tethering COPII and COPI vesicles respectively Theywork as GEF for Rab1 and the activation of this GTPasemight recruit other tethers (as p115 or COG) [177] Howeverthey do not interact directly with SNAREs It is possible thatthere is a cascade of tethering factors that facilitates cargotransport

6 Intra-Golgi Transport

The mode of transport across the GC remains controversialTwo main models have been proposed vesicular transportand cisternal maturation The first one proposes that Golgi

cisternae are static so that the cargo must move via vesiclesThe second model support that cisterna are dynamic struc-tures that move from the cis to trans Golgi sideThus accord-ing to this model the entire cisterna is the carrier In thesemodels COPI-coated vesicles are responsible for antero-grade and retrograde transport respectively (Figure 3) Sinceneither of these models explains all the experimental data acombination of the same models and new models have beenproposed (see below)

61 Vesicular Transport Model This model was launchedby Palade in 1975 and was widely accepted for many yearsbecause it provides a good explanation for the well-knowncompartmentalization of the Golgi resident enzymes In thismodel it is assumed that cisternae are stable compartmentsso that the cargo must leave one cisterna and move to thenext in order to advance through the stack This process ismediated by vesicles The model was strongly supported bythe discovery of COPI and COPII vesicles [182] COPI wereidentified in in vitro assays as being responsible for antero-grade transport between cisterna [107] In these cell-freeexperiments when the formation of COPI was inhibitedanterograde was blocked [183 184] On the other hand itwas clearly demonstrated that COPII vesicles are involved inER exit and transport to the GC [87] Soon it was assumedthat COPII and COPI vesicles act sequentially in the earlysecretory pathway that is ER-to-Golgi and intra-Golgitransport respectively However new experimental data castdoubt on the model First of all a clear role of COPI vesiclesin retrograde transport was demonstrated [120 185] To fitthese data with the model it was postulated that there weretwo types of COPI vesicles involved in anterograde and retro-grade transport at the Golgi stack [186] ldquoPercolatingrdquo COPIvesiclesmaymove bidirectionally up and down in the stack ina random way but allowing a net rate of flow of anterogradecargo in the cis-to-trans direction [187] However immuno-cytochemical [188] and proteomic [9] analysis of thesevesicles showed that they are mostly devoid of anterogradetransport markers Thus the role of COPI vesicles remainscontroversial [189] The small number of Golgi-associatedSNARE and Rab proteins also argues against multiple fusionevents between vesicles and every cisterna in the stacks Oneproblem is that this model does not explain the transport oflarge cargo such as procollagen (300 nm rigid rod) [190] oralgal scales (up to 15ndash2 120583m) [191] within 50ndash60 nm vesiclesInterestingly scales which are electron dense and can beeasily visualized are not observed within vesicles The exis-tence of megavesicles transporting large (gt400 nm) proteinaggregates has been described in an artificial system [192]but it is not clear that this a general mechanism used bynonmodified cells [190]

62 Cisternal Maturation Model This model was postu-lated in the early epoque of electron microscopy [193] andupdated as cisternal progression-maturation model [190194] According to this model cisternae are formed at thecis side of the GC by fusion of ER-derived membranes andthen these newly formed membranes move from the cis to

8 ISRN Cell Biology

Tubules Retrograde COPI vesicles

Cisternal maturation

Anterograde COPI vesicles

Retrograde COPI vesicles

Vesicular transport

Tubules

(a)

(b)

(c)

(d)

Figure 3 Putative role of COPI-coated vesicles and tubules according to vesicular transport and cisternal maturation models for intra-Golgitransport According to vesicular transport model cisternae are static Anterograde transport may be mediated by COPI-coated vesicles andtubular cisternal connections Another type of COPI-coated vesicles mediates retrograde transport (ie the retrieval of proteins that haveescaped from the endoplasmic reticulum) According to cisternal maturation model cisternae move from cis (a) to trans Golgi sides (d)COPI-coated vesicles and transient tubules may be involved in the recycling of Golgi resident proteins (retrograde transport)

the trans side where they become post-Golgi carriers Thusnewly formed cisterna gradually displaces older cisternaetowards the trans side In this model it is not necessary forthe cargo to leave the cisterna and the whole cisterna is takento act as a carrier This model explains the transport of largecargo and an analysis of procollagen transport fits this modelvery well [190] These large molecules are detected in largedistensions at the lateral edge of the cisterna in their transitthrough the stack These distensions are always connected

to the cisterna so that procollagen is not transported bylarge vesicles In contrast the model does not explain thepolarity of the stack and what happens with resident enzymeswhen cisternae disappear at the trans side To overcomethese problems it was assumed that Golgi resident enzymesare packed into COPI vesicles during cisternal progressionand transported backwards Thus Golgi enzymes are notlost but recycled in a trans-to-cis direction maintainingthe polarity of this organelle [195] The cisternae mature by

ISRN Cell Biology 9

acquiring and then losing specific Golgi-resident proteinsThe presence of Golgi resident enzymes in COPI vesicles hasbeen demonstrated [188] although their relative concentra-tion is controversial Life cell imaging studies in yeast stronglysupport this model In Saccharomyces cerevisiae the Golgiis not stacked so that individual cisterna can be analyzedseparately Using cis and trans Golgi markers it was directlydemonstrated that cisternae mature (ie the apparentlyconversion of one type of cisterna into another) [196 197]The cisternal maturation model seems to be more efficientgiven that it would seem easier to transport anterograde cargousing a large carrier (the cisterna) than to use many smallvesicles between adjacent cisternae and repeating this processseveral times until reaching the TGN It is also intuitive thatperi-Golgi vesicles should be restricted to more selective andsmaller trafficking the retrograde pathway

63 Alternative Models Given that none of these modelscompletely explains all the experimental data new modelshave been postulated although some of them are variationsof the two main models

Dual transport model one possibility is that these twomodels are not mutually exclusive but rather complementaryand working simultaneously [198] Cisternae may moveslowly whereas vesicles transport anterograde and retrogradecargo more rapidly Large molecules may use the cisternalmaturation mechanism while small molecules can be trans-ported using vesicular transport [186 198]

Rapid partitioning model This model is based on therapid partitioning of transmembrane cargo and residentenzymes between two lipid phases According to this modelthe GC works as a single compartment but contains pro-cessing and export domains [199] When the cargo reachesthe Golgi it associates with these domains and then leavesthe compartment from every level Again this model hasdifficulty in explaining the polarity of the cisternae and doesnot help visualize the Golgi stack as a single compartment

Kiss-and-runmodelThis model is based onmechanismsoperating in other systems such as endosomes and lysosomesThismodel proposes that two cisternaemay fuse to each otherthrough narrow tubules connecting their lumens transientlyand allowing the transit of cargo before separating [200] Inthis model anterograde transport and retrograde transportoccur simultaneously and a specific retrograde pathway is notnecessary This model may explain several aspects of Golgitransport including the transport of large molecules How-ever some assumptions of the model need to be confirmed(ig machinery and mechanisms for the fusion and fission ofconnections) It is also not clear how all the experimental dataabout the role of COPI coats in retrograde transport fit thismodel

Intra-Golgi transportmediated by tubulesThe absence ofcargo in COPI vesicles suggests that other transport interme-diates such as tubules may operate at the GC As mentionedabove tubules are a common structure surrounding the stackTubules may be involved in the anterograde movement ofcargo through this organelleThe ER and all cisternae may bedirectly connected by tubules and cargo might move along

the secretory pathway like food through the gut [201] Infact conditions that stimulated protein secretion increasethe number of tubular connections between cisternae [136137] Conversely tubules may establish transient connectionsbetween compartments helping COPI vesicles to transportGolgi enzymes retrogradely as indicated by the cisternalmaturation model [46] (Figure 3) Cisternal maturation inyeast occurs although slowly without COPI vesicles suggest-ing that tubules may replace them [197] Low temperature-induced Golgi tubules are enriched in Golgi enzymes andSNARE and Rab proteins involved in intra-Golgi transportwhereas they exclude other proteins associated with ER-Golgi transport [139] Whether the tubules found in thismodel are representative of the carriers involved in intra-Golgi transport remains to be established

7 Concluding Remarks

A century after the discovery of the ldquoapparato reticolareinternordquo [202] it is clear that no model for intra-Golgi trans-port explains all the experimental data But it is also true thatthe ldquohigh polarityrdquo that exits the field has stimulated intenseresearch Recently developed high-resolution methodologiesmay give important clues in this respect Of special interestis the analysis of the structure and composition of tubularand vesicular carriers High-resolution immunocytochemi-cal techniques in combination with electron tomography aswell as proteomic analysis of highly purified samples maysolve the problem or at least definitively reject some modelsIn the end it is possible that each cell type depending of itsspecial characteristics uses a givenmechanism of intra-Golgitransport It also remains possible that a single cell usesdifferent mechanisms of intra-Golgi transport depending onthe amount and type of cargo or its physiological statusMeanwhile cisternal maturation in combination with tubulartransient connections is a very attractive and intuitive modelthat seems to fit most experimental data

Acknowledgments

The work in this paper was supported by Grants fromthe Ministerio de Ciencia e Innovacion (Spain) ConsoliderCOAT (CSD2009-00016) and Fundacion Seneca de la Comu-nidadAutonoma de la Region deMurcia (04542GERM06)

References

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[2] W Nickel and C Rabouille ldquoMechanisms of regulated uncon-ventional protein secretionrdquo Nature Reviews Molecular CellBiology vol 10 no 2 pp 148ndash155 2009

[3] M G Farquhar and G E Palade ldquoThe Golgi apparatus (com-plex) (1954ndash1981) from artifact to center stagerdquo Journal of CellBiology vol 91 no 3 pp 77sndash103s 1981

[4] M G Farquhar and G E Palade ldquoThe Golgi apparatus 100years of progress and controversyrdquo Trends in Cell Biology vol8 no 1 pp 2ndash10 1998

10 ISRN Cell Biology

[5] C Wilson R Venditti L R Rega A Colanzi G DrsquoAngeloandM A De ldquoThe Golgi apparatus an organelle with multiplecomplex functionsrdquo Biochemical Journal vol 433 no 1 pp 1ndash92011

[6] J Lippincott-Schwartz E Snapp and A Kemvorthy ldquoStudyingprotein dynamics in living cellsrdquoNature Reviews Molecular CellBiology vol 2 no 6 pp 444ndash456 2001

[7] G Perinetti T Muller A Spaar R Polishchuk A Luini andA Egner ldquoCorrelation of 4Pi and electron microscopy to studytransport through single golgi stacks in living cells with superresolutionrdquo Traffic vol 10 no 4 pp 379ndash391 2009

[8] J Lippincott-Schwartz ldquoEmerging in vivo analyses of cellfunction using fluorescence imagingrdquo Annual Review of Bio-chemistry vol 80 pp 327ndash332 2011

[9] A Gilchrist C E Au J Hiding et al ldquoQuantitative proteomicsanalysis of the secretory pathwayrdquo Cell vol 127 no 6 pp 1265ndash1281 2006

[10] J Gannon J J Bergeron and T Nilsson ldquoGolgi and relatedvesicle proteomics simplify to identifyrdquo Cold Spring HarborPerspectives in Biology vol 3 no 12 2011

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[14] R S Polishchuk E V Polishchuk P Marra et al ldquoCorrelativelight-electron microscopy reveals the tubular-saccular ultra-structure of carriers operating between Golgi apparatus andplasma membranerdquo Journal of Cell Biology vol 148 no 1 pp45ndash58 2000

[15] B S Donohoe S Mogelsvang and L A Staehelin ldquoElectrontomography of ER Golgi and related membrane systemsrdquoMethods vol 39 no 2 pp 154ndash162 2006

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[17] M C Derby and P A Gleeson ldquoNew insights into membranetrafficking and protein sortingrdquo International Review of Cytol-ogy vol 261 pp 47ndash116 2007

[18] A A Mironov and M Pavelka The Golgi Apparatus State ofthe Art 110 Years after Camillo Golgirsquos Discovery Springer WienNewYork NY USA 2008

[19] E Papanikou and B S Glick ldquoThe yeast Golgi apparatusinsights and mysteriesrdquo FEBS Letters vol 583 no 23 pp 3746ndash3751 2009

[20] J H Wei and J Seemann ldquoMitotic division of the mammalianGolgi apparatusrdquo Seminars in Cell and Developmental Biologyvol 20 no 7 pp 810ndash816 2009

[21] M Anitei and B Hoflack ldquoExit from the trans-Golgi networkfrom molecules to mechanismsrdquo Current Opinion in Cell Biol-ogy vol 23 no 4 pp 443ndash451 2011

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[23] YWang and J Seemann ldquoGolgi biogenesisrdquoCold Spring HarborPerspectives in Biology vol 3 no 10 Article ID a005330 2011

[24] K W Moremen M Tiemeyer and A V Nairn ldquoVertebrateprotein glycosylation diversity synthesis and functionrdquoNatureReviews Molecular Cell Biology vol 13 pp 448ndash462 2012

[25] A J Dalton and M D Felix ldquoA comparative study of the Golgicomplexrdquo The Journal of Biophysical and Biochemical Cytologyvol 2 no 4 pp 79ndash84 1956

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[27] A Rambourg Y Clermont and L Hermo ldquoThree-dimensionalarchitecture of the Golgi apparatus in Sertoli cells of the ratrdquoAmerican Journal of Anatomy vol 154 no 4 pp 455ndash476 1979

[28] M S Ladinsky D NMastronarde J RMcIntosh K E Howelland L A Staehelin ldquoGolgi structure in three dimensionsfunctional insights from the normal rat kidney cellrdquo Journal ofCell Biology vol 144 no 6 pp 1135ndash1149 1999

[29] R S Taylor S M Jones R H Dahl M H Nordeen andK E Howell ldquoCharacterization of the Golgi complex clearedof proteins in transit and examination of calcium uptakeactivitiesrdquo Molecular Biology of the Cell vol 8 no 10 pp 1911ndash1931 1997

[30] MMWuM Grabe S Adams R Y Tsien H P HMoore andT E Machen ldquoMechanisms of pH regulation in the regulatedsecretory pathwayrdquo Journal of Biological Chemistry vol 276 no35 pp 33027ndash33035 2001

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[33] B Storrie JWhite S Rottger E H K Stelzer T Suganuma andT Nilsson ldquoRecycling of Golgi-resident glycosyltransferasesthrough the ER reveals a novel pathway and provides anexplanation for nocodazole-induced Golgi scatteringrdquo Journalof Cell Biology vol 143 no 6 pp 1505ndash1521 1998

[34] J Fan Z Hu L Zeng et al ldquoGolgi apparatus and neurode-generative diseasesrdquo International Journal of DevelopmentalNeuroscience vol 26 no 6 pp 523ndash534 2008

[35] Y Fujita EOhamaMTakatama S Al-Sarraj andKOkamotoldquoFragmentation of Golgi apparatus of nigral neurons with120572-synuclein-positive inclusions in patients with Parkinsonrsquosdiseaserdquo Acta Neuropathologica vol 112 no 3 pp 261ndash2652006

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[38] M G Farquhar and H P Hauri ldquoProtein sorting and vesiculartraffic in the Golgi apparatusrdquo inTheGolgi Apparatus E Bergerand J Roth Eds pp 63ndash128 Birkhauser Basel Switzerland1997

[39] G van Meer ldquoLipids of the Golgi membranerdquo Trends in CellBiology vol 8 no 1 pp 29ndash33 1998

[40] J C M Holthuis T Pomorski R J Raggers H Sprong andG Van Meer ldquoThe organizing potential of sphingolipids in

ISRN Cell Biology 11

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[45] A Rambourg and Y Clermont ldquoThree-dimensional structureof the Golgi apparatus in mammalian cellsrdquo in The GolgiApparatus E G Berger and J Roth Eds pp 37ndash61 BirkhauserBasel Switzerland 1997

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[52] R S Polishchuk andA AMironov ldquoStructural aspects of Golgifunctionrdquo Cellular andMolecular Life Sciences vol 61 no 2 pp146ndash158 2004

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[54] F Bard and V Malhotra ldquoThe formation of TGN-to-plasma-membrane transport carriersrdquo Annual Review of Cell andDevelopmental Biology vol 22 pp 439ndash455 2006

[55] R D Klausner J G Donaldson and J Lippincott-SchwartzldquoBrefeldin A insights into the control of membrane traffic andorganelle structurerdquo Journal of Cell Biology vol 116 no 5 pp1071ndash1080 1992

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[57] H HMollenhauer andD J Morre ldquoThe tubular network of theGolgi apparatusrdquo Histochemistry and Cell Biology vol 109 no5-6 pp 533ndash543 1998

[58] L Orci A Perrelet and J E Rothman ldquoVesicles on stringsMorphological evidence for processive transport within theGolgi stackrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 95 no 5 pp 2279ndash2283 1998

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12 ISRN Cell Biology

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[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

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[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

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BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

ISRN Cell Biology 5

ER-resident proteins [124 125] In this way soluble proteinsthat have escaped from the ER are retrieved Glycosylationenzymes may also require cargo adaptors [105]

4 Transport Carriers Tubules andHeterogenic Elements

For a long time it was assumed that membrane traffic ismediated by coated vesicles Although they play a key role inmany steps of the transport it is possible that coated vesiclesjust represent a fraction of the intermediate transport carriersoperating in the secretory pathway [126] Tubular elementson the other hand have been associated with all steps ofthe secretory pathway (Polishchuk and Mironov [52]) Thetransport of soluble [127] and transmembrane [99] cargofrom pre-Golgi elements to the Golgi is mediated by tubulesTubules are 20 of the elements operating at the ER-Golgiinterface [128] Post-Golgi carriers may also have a tubularform [129 130] In fact the TGN itself is often formed by anetwork of branching tubules

Tubules are also involved in intra-Golgi transport TheGC is associated to an extensive network of 30 nm-thicktubules connected to the lateral edges of the stacked cisternaeand may extend a considerable distance from the stacks [57]Golgi tubules were already observed in the first electronmicroscopical observations of this organelle [25] Early stud-ies showed tubular elements emerging from the Golgi stackand TGN connected to cisternae or oriented towards thecytoplasm [26 27] Hermo and coworkers [131] describedtubular connections between cisternae in the cis side of theGolgi apparatus of spermatids Despite this tubules werealmost forgotten in the field for decades probably due tothe difficulty of identifying them in bidimensional electronmicrographs (they only can be identified in longitudinalsections) This was exacerbated cisternal maturation modelbeing abandoned in favor of the vesicular transport modelResearch into these elements increased with the introductionof the drug brefeldin A in the study of the GC This druginduces extensive tubulation of this organelle Although thissystem is artificial it has been postulated that brefeldinA exaggerates the natural process of retrograde transportHowever in contrast with normal conditions this transportoccurs only after the dissociation of COPI coats from theGC The development of new methodologies such as time-lapse confocal microscopy or electron tomography hasreintroduced the idea that tubules are transport intermedi-ates Time-lapse analysis of living cells has shown tubulesemerging from the GC [132] containing GFP-tagged residentenzymes [133] or cargo [101 134] Electron tomography con-firms that these elements are commonly associated to theGC [28 135] In NRK cells there are tubules that emergefrom cis and trans cisternae suggesting that they are involvedin incoming and outgoing Golgi trafficking Tubules maygrow from all cisternae and may extend towards CGN andTGN Interestingly one single cisterna may contain tubulesoriented to both cis and trans faces [28] In cells stimulatedto increase the secretion rate tubular connections betweencisternae are evident [136 137] but these connections

disappear when cargo has left the GC Thus tubules mightreplace vesicles when there is an excess of cargo Tubules mayalso participate in the recycling of Golgi resident enzymesUnder low temperature (15∘C) conditions many tubulesemerge from theGC ofHeLa cellsThese tubules are enrichedin Golgi-resident enzymes and a specific set of SNAREand Rab proteins associated with intra-Golgi transport andcontain neither retrograde nor anterograde cargo [138 139]This type of tubule can also be observed under physiologicalconditions and they are good candidates for being consideredtransport intermediates at the Golgi level Several types oftubules with different functions may well exist

The molecular machinery involved in the formation ofGolgi tubules is just beginning to be known Based onbrefeldin A experiments tubular formation at the GC hasbeen related with the loss of COPI coats [140 141] GTP-bound ARF1 is able to induce Golgi tubules by insertion ofthe amino-terminal amphipathic helix [142] Microtubule-associated motor proteins are sufficient to induce tubulesfrom Golgi membranes [143] Some lipidic species such asphosphatidic acid diacylglycerol and lysophosphatidic acidfavor the curvature of membranes Thus enzymes associatedwith lipid metabolism play a key role in tubular formationLysophosphatidic acid generated by the enzyme phospho-lipase A2 has been involved in the retrograde transportmediated by tubules [144 145] Agonist and antagonist of thisenzyme increase or inhibit tubular formation respectivelyThis enzyme is involved in the formation of tubular continu-ities between cisternae [146] and tubular transport interme-diates at the TGN [147] The formation of transport carriersat the TGN is also diacylglycerol dependent This lipid isnecessary to recruit protein kinaseD a regulator of the fissionof transport carriers [54 148] Diacylglycerol has also beeninvolved in Golgi-to-ER retrograde transport mediated bytubules [149] Phosphatidic acid has been involved in intra-Golgi transport [150] Interestingly two lipid-modifyingenzymes lysophosphatidic acid acyltransferase-120574 and phos-pholipase A2-120572 which promote or inhibit COPI fissionrespectively work together regulating the morphology ofGolgi carriers [151] On the other hand the morphology ofpre-Golgi tubules depends on the cargo [128] COPI coatsmicrotubules and associated motor proteins [152] and alsothe activity of ARF and phospholipase A2 [153]Thus similarmachineries may be operating at different levels of the secre-tory pathway Interestingly live cell imaging shows that pre-Golgi elements may change their morphology very quicklyfrom vesicular to tubular form and vice versa [152]

Apart from the tubules other transport intermediates ofheterogeneous morphology have been described Polishchukand coworkers [154] described the formation of large tubulo-saccular elements involved in the microtubule-dependenttransport from the TGN to the plasma membrane The samegroup has described heterogenic membranes involved in ER-to-Golgi transport [155] Very large pleiomorphicmembrane-bound elements have also been associated with transportin the early secretory pathway [156] It seems that thereare different classes of transport carriers depending of theamount or type of cargo

6 ISRN Cell Biology

5 Molecular Machinery

In recent decades a huge amount of information has beenaccumulated about the molecular machinery involved inthe regulation of the intercompartmental transport in thesecretory pathway Most data refer to vesicles as transportcarriers but it can be assumed that the same or similar mech-anisms operate for other carriers If the formation of vesiclesand the selection of cargo depends on the coatmachinery thespecific targeting and fusion of the carriers with the targetmembranes depends on tethering factors Rab and SNAREproteins and other accessory proteins [157] In a simplemodel the rabs on incoming vesicles recruit tethering factorswhich permits SNARE complex formation

SNAREs (soluble N-ethylmaleimide-sensitive factorattachment proteins receptors) proteins are involved indocking and the specific fusion of transport intermediateswith the targetmembranes [157ndash159]The SNAREs associatedwith vesicles (or other transport intermediates) and targetmembranes have been named v- and t-SNARE respectivelyThis terminology however is not useful for describinghomotypic fusion events Structurally SNAREs have beendivided into R- and Q-SNAREs according to the centralresidue (RGln or QArg resp) of the SNARE domain aconserved region of 60ndash70 residues found in all members ofthis family Although there are some exceptions v-SNAREand t-SNARE are R-SNARE and Q-SNARE respectivelyInteraction between one v-SNARE and twothree t-SNAREinduces the formation of the trans-SNARE complex whichcatalyzes the fusion of the membranes SNARE proteins aresufficient to drive membrane fusion so that they are con-sidered the minimal membrane fusion machinery Afterfusion a cis-SNARE complex is formed in the target mem-branes This complex is later disassembled by the action ofthe cytosolic proteins 120572-SNAP (soluble N-ethylmaleimide-sensitive factor attachment protein) and the ATPase NSF(N-ethylmaleimide-sensitive factor) Now v-SNARE can betransported back to the donor compartment to be reusedSeveral SNARE complexes working at the secretoryendo-cytic pathway have been identified In mammalian cellstwo SNARE complexes have been implicated in intra-Golgitransport [160] A complex is formed of v-SNARE GS15 andthe t-SNAREs syntaxin5 GOS28 and Ykt6 is involved inCOPI-dependent intra-Golgi transport The second complexis formed of syntaxin 5 membrin (GS27) ERS24Sec22 andrBet1 the last one acting as v-SNARE This second complexhas been also involved in the fusion ER-derived elementswith the cis-Golgi and possible intra-Golgi transport Thedistribution of these SNAREs across the Golgi stack isdifferent Thus in general the components of the first com-plex increase in concentration toward the trans side whereasthe components of the second complex decrease [161]supporting the idea that these complexes mediate transportevents in opposite directions Syntaxin 5 which is present inboth complexes is distributed homogeneously through thestack SNARE complex assembly is regulated by SM (Sec1Munc18) proteins a family of cytosolic proteins Sly1 I isthe only member of this family operating at the ER-Golgiarea where it interacts with syntaxin 5 and syntaxin 18 at

the Golgi and ER respectively and controls anterograde andretrograde transport between these compartments [162]

Rab proteins are a family of small GTPases regulatingmembrane transport by recruiting effector proteins [159 163]They are localized at the cytoplasmic face of secretory andendocytic compartments and carriers and they have beenimplicated in vesicle budding uncoating mobility and trans-port Rab switches between an active form (GTP-bound) anda cytosolic inactive form (GDP-bound) Rab proteins in theGTP-bound form are reversibly associated with membranesby geranylgeranyl groups recruiting a variety of effectorsincluding sorting adaptors tethering factors kinases phos-phatases and motor proteins [163] The replacement of GDPby GTP is facilitated by guanine nucleotide exchange factors(GEFs) and their low intrinsic GTPase activity is enhancedby GTPase-activating proteins (GAP) Further regulation ofthe GTPGDP state and membrane association is providedby GDP dissociation inhibitor (GDI) and GDI displacementfactors (GDFs) Rab protein is a large family includingmore than 60 members in humans and 11 in yeast whichare specifically associated with distinct compartments andtransport events [163] Thus Rab proteins have also beenassociated with the control of membrane identity by control-ling local levels of phosphoinositides which concomitantlymay recruit specific proteins to certain compartments [164]The association of Rab proteins with specific membranes isguided by Rab escort protein (REP) which presents newlysynthesized Rab to geranylgeranyl transferase before target-ing the membranes The Golgi-associated Rab family playinga key role in Golgi maintenance and functioning includesRab1 Rab2 Rab6 Rab33B Rab18 and Rab43 [165] Rab1 andRab2 are involved in ER-to-Golgi transport Rab 1 is also veryimportant for Golgi ribbon maintenance Interestingly thelevels of expression or the distribution of this small GTPaseis affected in neurological disorders that show fragmentationof the Golgi ribbon [166] (Rendon et al [167]) Rab6 andmore specifically the Rab6AArsquo isoform is the most widelystudiedGolgi-associated Rab protein [168] It is important formaintaining Golgi structure and also for regulating transportin and out of the GC including a COPI-independent Golgi-to-ER transport [169] It is also associated with post-Golgicarriers where it recruits motor proteins [170 171] and alsoregulates the docking and fusion with the plasma membrane[172] At the Golgi stack it anchors the tethering factorsnecessary for attaching incoming vesicles The organizationof the Golgi ribbon the regulation of the number of cisternaein the stack and transport of coated vesicles is also associatedwith Rab6 and effectors [173] Rab33B is localized specificallyin the medial Golgi [174] where it is involved in Golgi-to-ER retrograde transport [175] Interestingly Rab6A recruitsspecific GEF that also interacts with Rab33B connecting theseRabs in a Rab cascade [176]Most probably Rab6 and Rab33Bwork together in the regulation of intra-Golgi and Golgi-to-ER transport [165] Less information is available about Rab43and Rab18 but they are also thought to be involved in ER-Golgi trafficking and Golgi organization

Tethering factors are a group of membrane-associatedproteins or multisubunit complexes that link transport vesi-cles with the targetmembranes to ensure correct docking and

ISRN Cell Biology 7

fusion They have recently been classified into three classesoligomeric complexes that work as Rab effectors and bindsSNARE oligomeric complexes that function as GEFs for Rabproteins and finally coiled-coil tethers [177] Proteins withextensive coiled-coil domains are long allowing long distancetethering These bridges not only facilitate the formation ofSNARE complexes but also may provide an initial specificityfor membrane fusionMembers of this family associated withthe Golgi are called golgins [178] In addition to tetheringthey have a role in Golgi stacking and form the Golgi matrixThis family includes p115 and GM130 the first of which isassociated with COPI and COPII vesicles the ERGIC andcis-Golgi membranes This protein is believed to be involvedin tethering of COPII vesicles to ERGIC membranes and thetransport events from these elements to the cis-Golgi It is alsopossible that it participates in transport between cisternaeThe recruitment of p115 to membranes is Rab1 dependentIt also interacts with ER-Golgi SNAREs COG subunits andother coiled-coil proteins such as GM130 and giantin Thesignificance of the last interaction is not clear GM130 isanother coiled-coil protein associated with the cis Golgi Itinteracts with many proteins including GRASP65 p115 Rab1Rab2 Rab33b and sintaxin5 P115 and GM130 are membersof the family of golgins which were first identified as Golgi-localized autoantigens using antibodies derived from thesera of patients with a variety of autoimmune disorders Asindicated above GM130 and p115 are also components ofthe Golgi matrix Apart from their role as tethers togetherwith other members of the golgin family such as GRASP65and giantin they are involved in maintaining the stackedmorphology of the cisterna and the Golgi ribbon [179]

Multisubunit complexes associated with the Golgiinclude Dsl1 COG and TRAPPIII [177] Dsl1 is a three-unitcomplex involved in Golgi-to-ER transport where it acts astethering COPI vesicles It interacts and stabilizes an SNAREcomplex at the ER The conserved oligomeric Golgi (COG)complex formed of 8 subunits (Cog1ndash8) found at the cis- andmedial Golgi cisternae is believed to be involved in transportto the Golgi and intra-Golgi recycling of Golgi resident pro-teins [180] Components of this tethering factor interactwith COPI components SNARE proteins (syntaxin 5) andcoiled-coil tether (p115) and are the effectors of several Rabproteins (Rab1 Rab6) Transport protein particle (TRAPP) isanother multisubunit complex that works as tethering factor[181] Two complexes have been identified TRAPP I andTRAPPII which are involved in entry and exit from theGC tethering COPII and COPI vesicles respectively Theywork as GEF for Rab1 and the activation of this GTPasemight recruit other tethers (as p115 or COG) [177] Howeverthey do not interact directly with SNAREs It is possible thatthere is a cascade of tethering factors that facilitates cargotransport

6 Intra-Golgi Transport

The mode of transport across the GC remains controversialTwo main models have been proposed vesicular transportand cisternal maturation The first one proposes that Golgi

cisternae are static so that the cargo must move via vesiclesThe second model support that cisterna are dynamic struc-tures that move from the cis to trans Golgi sideThus accord-ing to this model the entire cisterna is the carrier In thesemodels COPI-coated vesicles are responsible for antero-grade and retrograde transport respectively (Figure 3) Sinceneither of these models explains all the experimental data acombination of the same models and new models have beenproposed (see below)

61 Vesicular Transport Model This model was launchedby Palade in 1975 and was widely accepted for many yearsbecause it provides a good explanation for the well-knowncompartmentalization of the Golgi resident enzymes In thismodel it is assumed that cisternae are stable compartmentsso that the cargo must leave one cisterna and move to thenext in order to advance through the stack This process ismediated by vesicles The model was strongly supported bythe discovery of COPI and COPII vesicles [182] COPI wereidentified in in vitro assays as being responsible for antero-grade transport between cisterna [107] In these cell-freeexperiments when the formation of COPI was inhibitedanterograde was blocked [183 184] On the other hand itwas clearly demonstrated that COPII vesicles are involved inER exit and transport to the GC [87] Soon it was assumedthat COPII and COPI vesicles act sequentially in the earlysecretory pathway that is ER-to-Golgi and intra-Golgitransport respectively However new experimental data castdoubt on the model First of all a clear role of COPI vesiclesin retrograde transport was demonstrated [120 185] To fitthese data with the model it was postulated that there weretwo types of COPI vesicles involved in anterograde and retro-grade transport at the Golgi stack [186] ldquoPercolatingrdquo COPIvesiclesmaymove bidirectionally up and down in the stack ina random way but allowing a net rate of flow of anterogradecargo in the cis-to-trans direction [187] However immuno-cytochemical [188] and proteomic [9] analysis of thesevesicles showed that they are mostly devoid of anterogradetransport markers Thus the role of COPI vesicles remainscontroversial [189] The small number of Golgi-associatedSNARE and Rab proteins also argues against multiple fusionevents between vesicles and every cisterna in the stacks Oneproblem is that this model does not explain the transport oflarge cargo such as procollagen (300 nm rigid rod) [190] oralgal scales (up to 15ndash2 120583m) [191] within 50ndash60 nm vesiclesInterestingly scales which are electron dense and can beeasily visualized are not observed within vesicles The exis-tence of megavesicles transporting large (gt400 nm) proteinaggregates has been described in an artificial system [192]but it is not clear that this a general mechanism used bynonmodified cells [190]

62 Cisternal Maturation Model This model was postu-lated in the early epoque of electron microscopy [193] andupdated as cisternal progression-maturation model [190194] According to this model cisternae are formed at thecis side of the GC by fusion of ER-derived membranes andthen these newly formed membranes move from the cis to

8 ISRN Cell Biology

Tubules Retrograde COPI vesicles

Cisternal maturation

Anterograde COPI vesicles

Retrograde COPI vesicles

Vesicular transport

Tubules

(a)

(b)

(c)

(d)

Figure 3 Putative role of COPI-coated vesicles and tubules according to vesicular transport and cisternal maturation models for intra-Golgitransport According to vesicular transport model cisternae are static Anterograde transport may be mediated by COPI-coated vesicles andtubular cisternal connections Another type of COPI-coated vesicles mediates retrograde transport (ie the retrieval of proteins that haveescaped from the endoplasmic reticulum) According to cisternal maturation model cisternae move from cis (a) to trans Golgi sides (d)COPI-coated vesicles and transient tubules may be involved in the recycling of Golgi resident proteins (retrograde transport)

the trans side where they become post-Golgi carriers Thusnewly formed cisterna gradually displaces older cisternaetowards the trans side In this model it is not necessary forthe cargo to leave the cisterna and the whole cisterna is takento act as a carrier This model explains the transport of largecargo and an analysis of procollagen transport fits this modelvery well [190] These large molecules are detected in largedistensions at the lateral edge of the cisterna in their transitthrough the stack These distensions are always connected

to the cisterna so that procollagen is not transported bylarge vesicles In contrast the model does not explain thepolarity of the stack and what happens with resident enzymeswhen cisternae disappear at the trans side To overcomethese problems it was assumed that Golgi resident enzymesare packed into COPI vesicles during cisternal progressionand transported backwards Thus Golgi enzymes are notlost but recycled in a trans-to-cis direction maintainingthe polarity of this organelle [195] The cisternae mature by

ISRN Cell Biology 9

acquiring and then losing specific Golgi-resident proteinsThe presence of Golgi resident enzymes in COPI vesicles hasbeen demonstrated [188] although their relative concentra-tion is controversial Life cell imaging studies in yeast stronglysupport this model In Saccharomyces cerevisiae the Golgiis not stacked so that individual cisterna can be analyzedseparately Using cis and trans Golgi markers it was directlydemonstrated that cisternae mature (ie the apparentlyconversion of one type of cisterna into another) [196 197]The cisternal maturation model seems to be more efficientgiven that it would seem easier to transport anterograde cargousing a large carrier (the cisterna) than to use many smallvesicles between adjacent cisternae and repeating this processseveral times until reaching the TGN It is also intuitive thatperi-Golgi vesicles should be restricted to more selective andsmaller trafficking the retrograde pathway

63 Alternative Models Given that none of these modelscompletely explains all the experimental data new modelshave been postulated although some of them are variationsof the two main models

Dual transport model one possibility is that these twomodels are not mutually exclusive but rather complementaryand working simultaneously [198] Cisternae may moveslowly whereas vesicles transport anterograde and retrogradecargo more rapidly Large molecules may use the cisternalmaturation mechanism while small molecules can be trans-ported using vesicular transport [186 198]

Rapid partitioning model This model is based on therapid partitioning of transmembrane cargo and residentenzymes between two lipid phases According to this modelthe GC works as a single compartment but contains pro-cessing and export domains [199] When the cargo reachesthe Golgi it associates with these domains and then leavesthe compartment from every level Again this model hasdifficulty in explaining the polarity of the cisternae and doesnot help visualize the Golgi stack as a single compartment

Kiss-and-runmodelThis model is based onmechanismsoperating in other systems such as endosomes and lysosomesThismodel proposes that two cisternaemay fuse to each otherthrough narrow tubules connecting their lumens transientlyand allowing the transit of cargo before separating [200] Inthis model anterograde transport and retrograde transportoccur simultaneously and a specific retrograde pathway is notnecessary This model may explain several aspects of Golgitransport including the transport of large molecules How-ever some assumptions of the model need to be confirmed(ig machinery and mechanisms for the fusion and fission ofconnections) It is also not clear how all the experimental dataabout the role of COPI coats in retrograde transport fit thismodel

Intra-Golgi transportmediated by tubulesThe absence ofcargo in COPI vesicles suggests that other transport interme-diates such as tubules may operate at the GC As mentionedabove tubules are a common structure surrounding the stackTubules may be involved in the anterograde movement ofcargo through this organelleThe ER and all cisternae may bedirectly connected by tubules and cargo might move along

the secretory pathway like food through the gut [201] Infact conditions that stimulated protein secretion increasethe number of tubular connections between cisternae [136137] Conversely tubules may establish transient connectionsbetween compartments helping COPI vesicles to transportGolgi enzymes retrogradely as indicated by the cisternalmaturation model [46] (Figure 3) Cisternal maturation inyeast occurs although slowly without COPI vesicles suggest-ing that tubules may replace them [197] Low temperature-induced Golgi tubules are enriched in Golgi enzymes andSNARE and Rab proteins involved in intra-Golgi transportwhereas they exclude other proteins associated with ER-Golgi transport [139] Whether the tubules found in thismodel are representative of the carriers involved in intra-Golgi transport remains to be established

7 Concluding Remarks

A century after the discovery of the ldquoapparato reticolareinternordquo [202] it is clear that no model for intra-Golgi trans-port explains all the experimental data But it is also true thatthe ldquohigh polarityrdquo that exits the field has stimulated intenseresearch Recently developed high-resolution methodologiesmay give important clues in this respect Of special interestis the analysis of the structure and composition of tubularand vesicular carriers High-resolution immunocytochemi-cal techniques in combination with electron tomography aswell as proteomic analysis of highly purified samples maysolve the problem or at least definitively reject some modelsIn the end it is possible that each cell type depending of itsspecial characteristics uses a givenmechanism of intra-Golgitransport It also remains possible that a single cell usesdifferent mechanisms of intra-Golgi transport depending onthe amount and type of cargo or its physiological statusMeanwhile cisternal maturation in combination with tubulartransient connections is a very attractive and intuitive modelthat seems to fit most experimental data

Acknowledgments

The work in this paper was supported by Grants fromthe Ministerio de Ciencia e Innovacion (Spain) ConsoliderCOAT (CSD2009-00016) and Fundacion Seneca de la Comu-nidadAutonoma de la Region deMurcia (04542GERM06)

References

[1] G Palade ldquoIntracellular aspects of the process of protein syn-thesisrdquo Science vol 189 no 4200 pp 347ndash358 1975

[2] W Nickel and C Rabouille ldquoMechanisms of regulated uncon-ventional protein secretionrdquo Nature Reviews Molecular CellBiology vol 10 no 2 pp 148ndash155 2009

[3] M G Farquhar and G E Palade ldquoThe Golgi apparatus (com-plex) (1954ndash1981) from artifact to center stagerdquo Journal of CellBiology vol 91 no 3 pp 77sndash103s 1981

[4] M G Farquhar and G E Palade ldquoThe Golgi apparatus 100years of progress and controversyrdquo Trends in Cell Biology vol8 no 1 pp 2ndash10 1998

10 ISRN Cell Biology

[5] C Wilson R Venditti L R Rega A Colanzi G DrsquoAngeloandM A De ldquoThe Golgi apparatus an organelle with multiplecomplex functionsrdquo Biochemical Journal vol 433 no 1 pp 1ndash92011

[6] J Lippincott-Schwartz E Snapp and A Kemvorthy ldquoStudyingprotein dynamics in living cellsrdquoNature Reviews Molecular CellBiology vol 2 no 6 pp 444ndash456 2001

[7] G Perinetti T Muller A Spaar R Polishchuk A Luini andA Egner ldquoCorrelation of 4Pi and electron microscopy to studytransport through single golgi stacks in living cells with superresolutionrdquo Traffic vol 10 no 4 pp 379ndash391 2009

[8] J Lippincott-Schwartz ldquoEmerging in vivo analyses of cellfunction using fluorescence imagingrdquo Annual Review of Bio-chemistry vol 80 pp 327ndash332 2011

[9] A Gilchrist C E Au J Hiding et al ldquoQuantitative proteomicsanalysis of the secretory pathwayrdquo Cell vol 127 no 6 pp 1265ndash1281 2006

[10] J Gannon J J Bergeron and T Nilsson ldquoGolgi and relatedvesicle proteomics simplify to identifyrdquo Cold Spring HarborPerspectives in Biology vol 3 no 12 2011

[11] F Bard L Casano A Mallabiabarrena et al ldquoFunctionalgenomics reveals genes involved in protein secretion and Golgiorganizationrdquo Nature vol 439 pp 604ndash607 2006

[12] J W Slot and H J Geuze ldquoImmunoelectron microscopicexploration of theGolgi complexrdquo Journal ofHistochemistry andCytochemistry vol 31 no 8 pp 1049ndash1056 1983

[13] D ZeuschnerW J C Geerts E vanDonselaar et al ldquoImmuno-electron tomography of ER exit sites reveals the existence of freeCOPII-coated transport carriersrdquoNature Cell Biology vol 8 no4 pp 377ndash383 2006

[14] R S Polishchuk E V Polishchuk P Marra et al ldquoCorrelativelight-electron microscopy reveals the tubular-saccular ultra-structure of carriers operating between Golgi apparatus andplasma membranerdquo Journal of Cell Biology vol 148 no 1 pp45ndash58 2000

[15] B S Donohoe S Mogelsvang and L A Staehelin ldquoElectrontomography of ER Golgi and related membrane systemsrdquoMethods vol 39 no 2 pp 154ndash162 2006

[16] N K Gonatas A Stieber and J O Gonatas ldquoFragmentationof the Golgi apparatus in neurodegenerative diseases and celldeathrdquo Journal of the Neurological Sciences vol 246 no 1-2 pp21ndash30 2006

[17] M C Derby and P A Gleeson ldquoNew insights into membranetrafficking and protein sortingrdquo International Review of Cytol-ogy vol 261 pp 47ndash116 2007

[18] A A Mironov and M Pavelka The Golgi Apparatus State ofthe Art 110 Years after Camillo Golgirsquos Discovery Springer WienNewYork NY USA 2008

[19] E Papanikou and B S Glick ldquoThe yeast Golgi apparatusinsights and mysteriesrdquo FEBS Letters vol 583 no 23 pp 3746ndash3751 2009

[20] J H Wei and J Seemann ldquoMitotic division of the mammalianGolgi apparatusrdquo Seminars in Cell and Developmental Biologyvol 20 no 7 pp 810ndash816 2009

[21] M Anitei and B Hoflack ldquoExit from the trans-Golgi networkfrom molecules to mechanismsrdquo Current Opinion in Cell Biol-ogy vol 23 no 4 pp 443ndash451 2011

[22] J Klumperman ldquoArchitecture of the mammalian Golgirdquo ColdSpring Harbor Perspectives in Biology vol 3 no 7 Article IDa005181 2011

[23] YWang and J Seemann ldquoGolgi biogenesisrdquoCold Spring HarborPerspectives in Biology vol 3 no 10 Article ID a005330 2011

[24] K W Moremen M Tiemeyer and A V Nairn ldquoVertebrateprotein glycosylation diversity synthesis and functionrdquoNatureReviews Molecular Cell Biology vol 13 pp 448ndash462 2012

[25] A J Dalton and M D Felix ldquoA comparative study of the Golgicomplexrdquo The Journal of Biophysical and Biochemical Cytologyvol 2 no 4 pp 79ndash84 1956

[26] A Rambourg Y Clermont and A Marraud ldquoThree dimen-sional structure of the osmium impregnated Golgi apparatus asseen in the high voltage electronmicroscoperdquoAmerican Journalof Anatomy vol 140 no 1 pp 27ndash46 1974

[27] A Rambourg Y Clermont and L Hermo ldquoThree-dimensionalarchitecture of the Golgi apparatus in Sertoli cells of the ratrdquoAmerican Journal of Anatomy vol 154 no 4 pp 455ndash476 1979

[28] M S Ladinsky D NMastronarde J RMcIntosh K E Howelland L A Staehelin ldquoGolgi structure in three dimensionsfunctional insights from the normal rat kidney cellrdquo Journal ofCell Biology vol 144 no 6 pp 1135ndash1149 1999

[29] R S Taylor S M Jones R H Dahl M H Nordeen andK E Howell ldquoCharacterization of the Golgi complex clearedof proteins in transit and examination of calcium uptakeactivitiesrdquo Molecular Biology of the Cell vol 8 no 10 pp 1911ndash1931 1997

[30] MMWuM Grabe S Adams R Y Tsien H P HMoore andT E Machen ldquoMechanisms of pH regulation in the regulatedsecretory pathwayrdquo Journal of Biological Chemistry vol 276 no35 pp 33027ndash33035 2001

[31] J HWei and J Seemann ldquoUnraveling theGolgi ribbonrdquoTrafficvol 11 no 11 pp 1391ndash1400 2010

[32] A A Mironov and G V Beznoussenko ldquoMolecular mecha-nisms responsible for formation of Golgi ribbonrdquoHistology andHistopathology vol 26 no 1 pp 117ndash133 2011

[33] B Storrie JWhite S Rottger E H K Stelzer T Suganuma andT Nilsson ldquoRecycling of Golgi-resident glycosyltransferasesthrough the ER reveals a novel pathway and provides anexplanation for nocodazole-induced Golgi scatteringrdquo Journalof Cell Biology vol 143 no 6 pp 1505ndash1521 1998

[34] J Fan Z Hu L Zeng et al ldquoGolgi apparatus and neurode-generative diseasesrdquo International Journal of DevelopmentalNeuroscience vol 26 no 6 pp 523ndash534 2008

[35] Y Fujita EOhamaMTakatama S Al-Sarraj andKOkamotoldquoFragmentation of Golgi apparatus of nigral neurons with120572-synuclein-positive inclusions in patients with Parkinsonrsquosdiseaserdquo Acta Neuropathologica vol 112 no 3 pp 261ndash2652006

[36] G Thorne-Tjomsland M Dumontier and J C Jamiesonldquo3D topography of noncompact zone Golgi tubules in ratspermatids a computer-assisted serial section reconstructionstudyrdquoThe Anatomical Record vol 250 pp 381ndash396 1998

[37] A S Opat C Van Vliet and P A Gleeson ldquoTrafficking andlocalisation of residentGolgi glycosylation enzymesrdquoBiochimievol 83 no 8 pp 763ndash773 2001

[38] M G Farquhar and H P Hauri ldquoProtein sorting and vesiculartraffic in the Golgi apparatusrdquo inTheGolgi Apparatus E Bergerand J Roth Eds pp 63ndash128 Birkhauser Basel Switzerland1997

[39] G van Meer ldquoLipids of the Golgi membranerdquo Trends in CellBiology vol 8 no 1 pp 29ndash33 1998

[40] J C M Holthuis T Pomorski R J Raggers H Sprong andG Van Meer ldquoThe organizing potential of sphingolipids in

ISRN Cell Biology 11

intracellular membrane transportrdquo Physiological Reviews vol81 no 4 pp 1689ndash1723 2001

[41] D K Banfield ldquoMechanisms of protein retention in the GolgirdquoCold Spring Harbor Perspectives in Biology vol 3 Article IDa005264 2011

[42] D J Gill J Chia J Senewiratne and F Bard ldquoRegulation ofO-glycosylation through Golgi-to-ER relocation of initiationenzymesrdquo Journal of Cell Biology vol 189 no 5 pp 843ndash8582010

[43] A Sesso F Paulo de Faria E S M Iwamura and H Correa ldquoAthree-dimensional reconstruction study of the rough ER-Golgiinterface in serial thin sections of the pancreatic acinar cell ofthe ratrdquo Journal of Cell Science vol 107 no 3 pp 517ndash528 1994

[44] Y Clermont A Rambourg and L Hermo ldquoConnectionsbetween the various elements of the cis- and mid-compart-ments of the Golgi apparatus of early rat spermatidsrdquo Anatomi-cal Record vol 240 no 4 pp 469ndash480 1994

[45] A Rambourg and Y Clermont ldquoThree-dimensional structureof the Golgi apparatus in mammalian cellsrdquo in The GolgiApparatus E G Berger and J Roth Eds pp 37ndash61 BirkhauserBasel Switzerland 1997

[46] G Vivero-Salmeron J Ballesta and J A Martınez-MenarguezldquoHeterotypic tubular connections at the endoplasmic reticu-lum-Golgi complex interfacerdquo Histochemistry and Cell Biologyvol 130 pp 709ndash717 2008

[47] C vanVliet E CThomas AMerino-Trigo R D Teasdale andP A Gleeson ldquoIntracellular sorting and transport of proteinsrdquoProgress in Biophysics and Molecular Biology vol 83 no 1 pp1ndash45 2003

[48] G Griffiths S Pfeiffer K Simons and K Matlin ldquoExit of newlysynthesized membrane proteins from the trans cisterna of theGolgi complex to the plasmamembranerdquo Journal of Cell Biologyvol 101 no 3 pp 949ndash964 1985

[49] G Griffiths S D Fuller R BackMHollinshead S Pfeiffer andK Simons ldquoThe dynamic nature of the Golgi complexrdquo Journalof Cell Biology vol 108 no 2 pp 277ndash297 1989

[50] H J Geuze and D J Morre ldquoTrans-Golgi reticulumrdquo Journal ofElectron Microscopy Technique vol 17 no 1 pp 24ndash34 1991

[51] Y Clermont A Rambourg and L Hermo ldquoTrans-Golgi net-work (TGN) of different cell types three-dimensional structuralcharacteristics and variabilityrdquo Anatomical Record vol 242 no3 pp 289ndash301 1995

[52] R S Polishchuk andA AMironov ldquoStructural aspects of Golgifunctionrdquo Cellular andMolecular Life Sciences vol 61 no 2 pp146ndash158 2004

[53] P A Gleeson J G Lock M R Luke and J L Stow ldquoDomainsof the TGN coats tethers and G proteinsrdquo Traffic vol 5 no 5pp 315ndash326 2004

[54] F Bard and V Malhotra ldquoThe formation of TGN-to-plasma-membrane transport carriersrdquo Annual Review of Cell andDevelopmental Biology vol 22 pp 439ndash455 2006

[55] R D Klausner J G Donaldson and J Lippincott-SchwartzldquoBrefeldin A insights into the control of membrane traffic andorganelle structurerdquo Journal of Cell Biology vol 116 no 5 pp1071ndash1080 1992

[56] J Llopis J M McCaffery A Miyawaki M G Farquhar andR Y Tsien ldquoMeasurement of cytosolic mitochondrial andGolgi pH in single living cells with green fluorescent proteinsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 12 pp 6803ndash6808 1998

[57] H HMollenhauer andD J Morre ldquoThe tubular network of theGolgi apparatusrdquo Histochemistry and Cell Biology vol 109 no5-6 pp 533ndash543 1998

[58] L Orci A Perrelet and J E Rothman ldquoVesicles on stringsMorphological evidence for processive transport within theGolgi stackrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 95 no 5 pp 2279ndash2283 1998

[59] Y Xiang and Y Wang ldquoNew components of the Golgi matrixrdquoCell and Tissue Research vol 344 no 3 pp 365ndash379 2011

[60] N Nakamura C Rabouille R Watson et al ldquoCharacterizationof a cis-Golgi matrix protein GM130rdquo Journal of Cell Biologyvol 131 no 6 pp 1715ndash1726 1995

[61] P Slusarewicz T Nilsson N Hui R Watson and G WarrenldquoIsolation of amatrix that bindsmedial Golgi enzymesrdquo Journalof Cell Biology vol 124 no 4 pp 405ndash413 1994

[62] G Egea and R M Rios ldquoThe role of the cytoskeleton in thestructure and function of the Golgi apparatusrdquo in The GolgiApparatus A A Mironov and M Pavelka Eds pp 270ndash300Springer NewYork NY USA 2008

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[64] R M Rios and M Bornens ldquoThe Golgi apparatus at the cellcentrerdquoCurrent Opinion in Cell Biology vol 15 pp 60ndash66 2003

[65] S Yadav and A D Linstedt ldquoGolgi positioningrdquo Cold SpringHarbor Perspectives in Biology vol 3 pp 1ndash17 2011

[66] J K Burkhardt ldquoThe role of microtubule-based motor proteinsin maintaining the structure and function of the Golgi com-plexrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp 113ndash126 1998

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[68] S Rivero J Cardenas M Bornens and R M Rios ldquoMicro-tubule nucleation at the cis-side of the golgi apparatus requiresAKAP450 and GM130rdquo The EMBO Journal vol 28 no 8 pp1016ndash1028 2009

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[70] P M Miller A W Folkmann A R R Maia N EfimovaA Efimov and I Kaverina ldquoGolgi-derived CLASP-dependentmicrotubules control Golgi organization and polarized traffick-ing in motile cellsrdquo Nature Cell Biology vol 11 no 9 pp 1069ndash1080 2009

[71] F Valderrama A Luna T Babia et al ldquoThe Golgi-associatedCOPI-coated buds and vesicles contain 120573120574-actinrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 97 no 4 pp 1560ndash1565 2000

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[74] F Valderrama J M Duran T Babia H Barth J Renau-Piqueras and G Egea ldquoActin microfilaments facilitate theretrogade transport from the Golgi complex to the endoplasmicreticulum in mammalian cellsrdquo Traffic vol 2 no 10 pp 717ndash726 2001

12 ISRN Cell Biology

[75] A Disanza and G Scita ldquoCytoskeletal regulation coordinatingactin and microtubule dynamics in membrane traffickingrdquoCurrent Biology vol 18 no 18 pp R873ndashR875 2008

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[77] Q T Shen P P Hsiue C V Sindelar M D Welch KG Campellone and H W Wang ldquoStructural insights intoWHAMM-mediated cytoskeletal coordination during mem-brane remodelingrdquoThe Journal of Cell Biology vol 199 pp 111ndash124 2012

[78] T F Roth and K R Porter ldquoYolk protein uptake in the oocyteof the mosquito Aedes aegypti Lrdquo The Journal of Cell Biologyvol 20 pp 313ndash332 1964

[79] B M F Pearse ldquoClathrin a unique protein associated withintracellular transfer of membrane by coated vesiclesrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 73 no 4 pp 1255ndash1259 1976

[80] A Oprins R Duden T E Kreis H J Geuze and J W Slotldquo120573-COP localizes mainly to the cis-Golgi side in exocrinepancreasrdquo Journal of Cell Biology vol 121 no 1 pp 49ndash60 1993

[81] B M F Pearse and M S Robinson ldquoClathrin adaptors andsortingrdquo Annual Review of Cell Biology vol 6 pp 151ndash171 1990

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[83] T Kirchhausen ldquoClathrinrdquo Annual Review of Biochemistry vol69 pp 699ndash727 2000

[84] E Rodriguez-Boulan and A Musch ldquoProtein sorting in theGolgi complex shifting paradigmsrdquo Biochimica et BiophysicaActa vol 1744 no 3 pp 455ndash464 2005

[85] M A McNiven H Cao K R Pitts and Y Yoon ldquoThe dynaminfamily of mechanoenzymes pinching in new placesrdquo Trends inBiochemical Sciences vol 25 no 3 pp 115ndash120 2000

[86] E Eisenberg and L E Greene ldquoMultiple roles of auxilin andHsc70 in clathrin-mediated endocytosisrdquo Traffic vol 8 no 6pp 640ndash646 2007

[87] C Barlowe L Orci T Yeung et al ldquoCOPII a membrane coatformed by sec proteins that drive vesicle budding from theendoplasmic reticulumrdquo Cell vol 77 no 6 pp 895ndash907 1994

[88] L C Bickford E Mossessova and J Goldberg ldquoA structuralview of the COPII vesicle coatrdquo Current Opinion in StructuralBiology vol 14 no 2 pp 147ndash153 2004

[89] D Jensen and R Schekman ldquoCOPII-mediated vesicle forma-tion at a glancerdquo Journal of Cell Science vol 124 no 1 pp 1ndash42011

[90] T Kirchhausen ldquoMaking COPII coatsrdquo Cell vol 129 no 7 pp1251ndash1252 2007

[91] C Barlowe ldquoCOPII and selective export from the endoplasmicreticulumrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp67ndash76 1998

[92] J A Martınez-Menarguez H J Geuze J W Slot and JKlumperman ldquoVesicular tubular clusters between the ER andGolgi mediate concentration of soluble secretory proteins byexclusion fromCOPI-coated vesiclesrdquoCell vol 98 no 1 pp 81ndash90 1999

[93] K Saito M Chen F Bard et al ldquoTANGO1 facilitates cargoloading at endoplasmic reticulum exit sitesrdquo Cell vol 136 no5 pp 891ndash902 2009

[94] L Jin K B Pahuja K E Wickliffe et al ldquoUbiquitin-dependentregulation of COPII coat size and functionrdquo Nature vol 482pp 495ndash500 2012

[95] H P Hauri and A Schweizer ldquoThe endoplasmic reticulum-Golgi intermediate compartmentrdquo Current Opinion in CellBiology vol 4 no 4 pp 600ndash608 1992

[96] S I Bannykh T Rowe and W E Balch ldquoThe organizationof endoplasmic reticulum export complexesrdquo Journal of CellBiology vol 135 no 1 pp 19ndash35 1996

[97] J Saraste and E Kuismanen ldquoPre- and post-Golgi vacuolesoperate in the transport of Semliki Forest virus membraneglycoproteins to the cell surfacerdquo Cell vol 38 no 2 pp 535ndash549 1984

[98] A Schweizer J A M Fransen K Matter T E Kreis L GinselandH PHauri ldquoIdentification of an intermediate compartmentinvolved in protein transport from endoplasmic reticulum toGolgi apparatusrdquo European Journal of Cell Biology vol 53 no 2pp 185ndash196 1990

[99] H Ben-Takaya K Miura R Pepperkok and H P Hauri ldquoLiveimaging of bidirectional traffic from the ERGICrdquo Journal of CellScience vol 118 no 2 pp 357ndash367 2005

[100] Y C Zhang Y Zhou C Z Yang and D S Xiong ldquoA reviewof ERGIC-53 its structure functions regulation and relationswith diseasesrdquo Histology and Histopathology vol 24 no 9 pp1193ndash1204 2009

[101] J F Presley N B Cole T A Schroer K Hirschberg K JM Zaal and J Lippincott-Schwartz ldquoER-to-Golgi transportvisualized in living cellsrdquo Nature vol 389 no 6646 pp 81ndash851997

[102] J A Martınez-Menarguez H J Geuze and J Ballesta ldquoIdenti-fication of two types of beta-COP vesicles in the Golgi complexof rat spermatidsrdquo European Journal of Cell Biology vol 71 pp137ndash143 1996

[103] J Lippincott-Schwartz J G Donaldson A Schweizer et alldquoMicrotubule-dependent retrograde transport of proteins intothe ER in the presence of brefeldin A suggests an ER recyclingpathwayrdquo Cell vol 60 no 5 pp 821ndash836 1990

[104] A Girod B Storrie J C Simpson et al ldquoEvidence for a COP-I-independent transport route from the Golgi complex to theendoplasmic reticulumrdquo Nature Cell Biology vol 1 no 7 pp423ndash430 1999

[105] V Popoff F Adolf B Brugger and F Wieland ldquoCOPI buddingwithin the Golgi stackrdquo Cold Spring Harbor Perspectives inBiology vol 3 Article ID a005231 2011

[106] J Moelleken J Malsam M J Betts et al ldquoDifferential localiza-tion of coatomer complex isoforms within the Golgi apparatusrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 104 no 11 pp 4425ndash4430 2007

[107] L Orci B S Glick and J E Rothman ldquoA new type of coatedvesicular carrier that appears not to contain clathrin its possiblerole in protein transport within theGolgi stackrdquoCell vol 46 no2 pp 171ndash184 1986

[108] V Malhotra T Serafini L Orci J C Shepherd and J ERothman ldquoPurification of a novel class of coated vesiclesmediating biosynthetic protein transport through the Golgistackrdquo Cell vol 58 no 2 pp 329ndash336 1989

[109] M G Waters T Serafini and J E Rothman ldquolsquoCoatomerrsquo acytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesiclesrdquo Nature vol 349 no 6306 pp248ndash251 1991

[110] T Serafini L Orci M Amherdt M Brunner R A Kahn andJ E Rothman ldquoADP-ribosylation factor is a subunit of the coatof Golgi-derived COP-coated vesicles a novel role for a GTP-binding proteinrdquo Cell vol 67 no 2 pp 239ndash253 1991

ISRN Cell Biology 13

[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

[112] K Kawamoto Y Yoshida H Tamaki et al ldquoGBF1 a guaninenucleotide exchange factor for ADP-ribosylation factors islocalized to the cis-Golgi and involved inmembrane associationof the COPI coatrdquo Traffic vol 3 no 7 pp 483ndash495 2002

[113] R Garcıa-Mata T Szul C Alvarez and E Sztul ldquoADP-ribosylation factorCOPI-dependent events at the endoplas-mic reticulum-Golgi interface are regulated by the guaninenucleotide exchange factor GBF1rdquoMolecular Biology of the Cellvol 14 no 6 pp 2250ndash2261 2003

[114] H Inoue and P A Randazzo ldquoArf GAPs and their interactingproteinsrdquo Traffic vol 8 no 11 pp 1465ndash1475 2007

[115] G Tanigawa L Orci M Amherdt M Ravazzola J B Helmsand J E Rothman ldquoHydrolysis of bound GTP by ARF proteintriggers uncoating of Golgi- derived COP-coated vesiclesrdquoJournal of Cell Biology vol 123 no 6 pp 1365ndash1371 1993

[116] Y Shiba and P A Randazzo ldquoArfGAP1 function in COPImediated membrane traffic currently debated models andcomparison to other coat-binding ArfGAPsrdquo Histology andHistopathology vol 27 pp 1143ndash1153 2012

[117] J Bigay P Gounon S Roblneau and B Antonny ldquoLipidpacking sensed by ArfGAP1 couples COPI coat disassembly tomembrane bilayer curvaturerdquo Nature vol 426 no 6966 pp563ndash566 2003

[118] W Nickel J Malsam K Gorgas et al ldquoUptake by COPI-coatedvesicles of both anterograde and retrograde cargo is inhibitedby GTP120574S in vitrordquo Journal of Cell Science vol 111 no 20 pp3081ndash3090 1998

[119] R Beck M Rawet F T Wieland and D Cassel ldquoThe COPIsystemmolecularmechanisms and functionrdquo FEBS Letters vol583 pp 2701ndash2709 2009

[120] F Letourneur E C Gaynor S Hennecke et al ldquoCoatomeris essential for retrieval of dilysine-tagged proteins to theendoplasmic reticulumrdquo Cell vol 79 no 7 pp 1199ndash1207 1994

[121] R Schindler C Itin M Zerial F Lottspeich and H P HaurildquoERGIC-53 a membrane protein of the ER-Golgi intermediatecompartment carries an ER retention motifrdquo European Journalof Cell Biology vol 61 no 1 pp 1ndash9 1993

[122] L P Jackson M Lewis H M Kent et al ldquoMolecular basis forrecognition of dilysine trafficking motifs by COPIrdquo Develop-mental Cell vol 23 pp 1ndash8 2012

[123] W Nickel K Sohn C Bunning and F T Wieland ldquop23 Amajor COPI-vesicle membrane protein constitutively cyclesthrough the early secretory pathwayrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 94 no21 pp 11393ndash11398 1997

[124] J C Semenza K G Hardwick N Dean and H R BPelham ldquoERD2 a yeast gene required for the receptor-mediatedretrieval of luminal ER proteins from the secretory pathwayrdquoCell vol 61 no 7 pp 1349ndash1357 1990

[125] I Majoul M Straub S W Hell R Duden and H D SolingldquoKDEL-cargo regulates interactions between proteins involvedin COPI vesicle traffic measurements in living cells usingFRETrdquo Developmental Cell vol 1 no 1 pp 139ndash153 2001

[126] B S Glick ldquoOrganization of the Golgi apparatusrdquo CurrentOpinion in Cell Biology vol 12 no 4 pp 450ndash456 2000

[127] R Blum D J Stephens and I Schulz ldquoLumenal targeted GFPused as a marker of soluble cargo visualises rapid ERGIC toGolgi traffic by a tubulo-vesicular networkrdquo Journal of CellScience vol 113 no 18 pp 3151ndash3159 2000

[128] J C Simpson T Nilsson and R Pepperkok ldquoBiogenesis oftubular ER-to-golgi transport intermediatesrdquoMolecular Biologyof the Cell vol 17 no 2 pp 723ndash737 2006

[129] K Hirschberg C M Miller J Ellenberg et al ldquoKinetic analysisof secretory protein traffic and characterization of Golgi toplasma membrane transport intermediates in living cellsrdquoJournal of Cell Biology vol 143 no 6 pp 1485ndash1503 1998

[130] D Toomre P Keller JWhite J C Olivo and K Simons ldquoDual-color visualization of trans-Golgi network to plasmamembranetraffic alongmicrotubules in living cellsrdquo Journal of Cell Sciencevol 112 no 1 pp 21ndash33 1999

[131] L Hermo A Rambourg and Y Clermont ldquoThree-dimensionalarchitecture of the cortical region of the Golgi apparatus in ratspermatidsrdquo American Journal of Anatomy vol 157 no 4 pp357ndash373 1980

[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

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BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

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Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

6 ISRN Cell Biology

5 Molecular Machinery

In recent decades a huge amount of information has beenaccumulated about the molecular machinery involved inthe regulation of the intercompartmental transport in thesecretory pathway Most data refer to vesicles as transportcarriers but it can be assumed that the same or similar mech-anisms operate for other carriers If the formation of vesiclesand the selection of cargo depends on the coatmachinery thespecific targeting and fusion of the carriers with the targetmembranes depends on tethering factors Rab and SNAREproteins and other accessory proteins [157] In a simplemodel the rabs on incoming vesicles recruit tethering factorswhich permits SNARE complex formation

SNAREs (soluble N-ethylmaleimide-sensitive factorattachment proteins receptors) proteins are involved indocking and the specific fusion of transport intermediateswith the targetmembranes [157ndash159]The SNAREs associatedwith vesicles (or other transport intermediates) and targetmembranes have been named v- and t-SNARE respectivelyThis terminology however is not useful for describinghomotypic fusion events Structurally SNAREs have beendivided into R- and Q-SNAREs according to the centralresidue (RGln or QArg resp) of the SNARE domain aconserved region of 60ndash70 residues found in all members ofthis family Although there are some exceptions v-SNAREand t-SNARE are R-SNARE and Q-SNARE respectivelyInteraction between one v-SNARE and twothree t-SNAREinduces the formation of the trans-SNARE complex whichcatalyzes the fusion of the membranes SNARE proteins aresufficient to drive membrane fusion so that they are con-sidered the minimal membrane fusion machinery Afterfusion a cis-SNARE complex is formed in the target mem-branes This complex is later disassembled by the action ofthe cytosolic proteins 120572-SNAP (soluble N-ethylmaleimide-sensitive factor attachment protein) and the ATPase NSF(N-ethylmaleimide-sensitive factor) Now v-SNARE can betransported back to the donor compartment to be reusedSeveral SNARE complexes working at the secretoryendo-cytic pathway have been identified In mammalian cellstwo SNARE complexes have been implicated in intra-Golgitransport [160] A complex is formed of v-SNARE GS15 andthe t-SNAREs syntaxin5 GOS28 and Ykt6 is involved inCOPI-dependent intra-Golgi transport The second complexis formed of syntaxin 5 membrin (GS27) ERS24Sec22 andrBet1 the last one acting as v-SNARE This second complexhas been also involved in the fusion ER-derived elementswith the cis-Golgi and possible intra-Golgi transport Thedistribution of these SNAREs across the Golgi stack isdifferent Thus in general the components of the first com-plex increase in concentration toward the trans side whereasthe components of the second complex decrease [161]supporting the idea that these complexes mediate transportevents in opposite directions Syntaxin 5 which is present inboth complexes is distributed homogeneously through thestack SNARE complex assembly is regulated by SM (Sec1Munc18) proteins a family of cytosolic proteins Sly1 I isthe only member of this family operating at the ER-Golgiarea where it interacts with syntaxin 5 and syntaxin 18 at

the Golgi and ER respectively and controls anterograde andretrograde transport between these compartments [162]

Rab proteins are a family of small GTPases regulatingmembrane transport by recruiting effector proteins [159 163]They are localized at the cytoplasmic face of secretory andendocytic compartments and carriers and they have beenimplicated in vesicle budding uncoating mobility and trans-port Rab switches between an active form (GTP-bound) anda cytosolic inactive form (GDP-bound) Rab proteins in theGTP-bound form are reversibly associated with membranesby geranylgeranyl groups recruiting a variety of effectorsincluding sorting adaptors tethering factors kinases phos-phatases and motor proteins [163] The replacement of GDPby GTP is facilitated by guanine nucleotide exchange factors(GEFs) and their low intrinsic GTPase activity is enhancedby GTPase-activating proteins (GAP) Further regulation ofthe GTPGDP state and membrane association is providedby GDP dissociation inhibitor (GDI) and GDI displacementfactors (GDFs) Rab protein is a large family includingmore than 60 members in humans and 11 in yeast whichare specifically associated with distinct compartments andtransport events [163] Thus Rab proteins have also beenassociated with the control of membrane identity by control-ling local levels of phosphoinositides which concomitantlymay recruit specific proteins to certain compartments [164]The association of Rab proteins with specific membranes isguided by Rab escort protein (REP) which presents newlysynthesized Rab to geranylgeranyl transferase before target-ing the membranes The Golgi-associated Rab family playinga key role in Golgi maintenance and functioning includesRab1 Rab2 Rab6 Rab33B Rab18 and Rab43 [165] Rab1 andRab2 are involved in ER-to-Golgi transport Rab 1 is also veryimportant for Golgi ribbon maintenance Interestingly thelevels of expression or the distribution of this small GTPaseis affected in neurological disorders that show fragmentationof the Golgi ribbon [166] (Rendon et al [167]) Rab6 andmore specifically the Rab6AArsquo isoform is the most widelystudiedGolgi-associated Rab protein [168] It is important formaintaining Golgi structure and also for regulating transportin and out of the GC including a COPI-independent Golgi-to-ER transport [169] It is also associated with post-Golgicarriers where it recruits motor proteins [170 171] and alsoregulates the docking and fusion with the plasma membrane[172] At the Golgi stack it anchors the tethering factorsnecessary for attaching incoming vesicles The organizationof the Golgi ribbon the regulation of the number of cisternaein the stack and transport of coated vesicles is also associatedwith Rab6 and effectors [173] Rab33B is localized specificallyin the medial Golgi [174] where it is involved in Golgi-to-ER retrograde transport [175] Interestingly Rab6A recruitsspecific GEF that also interacts with Rab33B connecting theseRabs in a Rab cascade [176]Most probably Rab6 and Rab33Bwork together in the regulation of intra-Golgi and Golgi-to-ER transport [165] Less information is available about Rab43and Rab18 but they are also thought to be involved in ER-Golgi trafficking and Golgi organization

Tethering factors are a group of membrane-associatedproteins or multisubunit complexes that link transport vesi-cles with the targetmembranes to ensure correct docking and

ISRN Cell Biology 7

fusion They have recently been classified into three classesoligomeric complexes that work as Rab effectors and bindsSNARE oligomeric complexes that function as GEFs for Rabproteins and finally coiled-coil tethers [177] Proteins withextensive coiled-coil domains are long allowing long distancetethering These bridges not only facilitate the formation ofSNARE complexes but also may provide an initial specificityfor membrane fusionMembers of this family associated withthe Golgi are called golgins [178] In addition to tetheringthey have a role in Golgi stacking and form the Golgi matrixThis family includes p115 and GM130 the first of which isassociated with COPI and COPII vesicles the ERGIC andcis-Golgi membranes This protein is believed to be involvedin tethering of COPII vesicles to ERGIC membranes and thetransport events from these elements to the cis-Golgi It is alsopossible that it participates in transport between cisternaeThe recruitment of p115 to membranes is Rab1 dependentIt also interacts with ER-Golgi SNAREs COG subunits andother coiled-coil proteins such as GM130 and giantin Thesignificance of the last interaction is not clear GM130 isanother coiled-coil protein associated with the cis Golgi Itinteracts with many proteins including GRASP65 p115 Rab1Rab2 Rab33b and sintaxin5 P115 and GM130 are membersof the family of golgins which were first identified as Golgi-localized autoantigens using antibodies derived from thesera of patients with a variety of autoimmune disorders Asindicated above GM130 and p115 are also components ofthe Golgi matrix Apart from their role as tethers togetherwith other members of the golgin family such as GRASP65and giantin they are involved in maintaining the stackedmorphology of the cisterna and the Golgi ribbon [179]

Multisubunit complexes associated with the Golgiinclude Dsl1 COG and TRAPPIII [177] Dsl1 is a three-unitcomplex involved in Golgi-to-ER transport where it acts astethering COPI vesicles It interacts and stabilizes an SNAREcomplex at the ER The conserved oligomeric Golgi (COG)complex formed of 8 subunits (Cog1ndash8) found at the cis- andmedial Golgi cisternae is believed to be involved in transportto the Golgi and intra-Golgi recycling of Golgi resident pro-teins [180] Components of this tethering factor interactwith COPI components SNARE proteins (syntaxin 5) andcoiled-coil tether (p115) and are the effectors of several Rabproteins (Rab1 Rab6) Transport protein particle (TRAPP) isanother multisubunit complex that works as tethering factor[181] Two complexes have been identified TRAPP I andTRAPPII which are involved in entry and exit from theGC tethering COPII and COPI vesicles respectively Theywork as GEF for Rab1 and the activation of this GTPasemight recruit other tethers (as p115 or COG) [177] Howeverthey do not interact directly with SNAREs It is possible thatthere is a cascade of tethering factors that facilitates cargotransport

6 Intra-Golgi Transport

The mode of transport across the GC remains controversialTwo main models have been proposed vesicular transportand cisternal maturation The first one proposes that Golgi

cisternae are static so that the cargo must move via vesiclesThe second model support that cisterna are dynamic struc-tures that move from the cis to trans Golgi sideThus accord-ing to this model the entire cisterna is the carrier In thesemodels COPI-coated vesicles are responsible for antero-grade and retrograde transport respectively (Figure 3) Sinceneither of these models explains all the experimental data acombination of the same models and new models have beenproposed (see below)

61 Vesicular Transport Model This model was launchedby Palade in 1975 and was widely accepted for many yearsbecause it provides a good explanation for the well-knowncompartmentalization of the Golgi resident enzymes In thismodel it is assumed that cisternae are stable compartmentsso that the cargo must leave one cisterna and move to thenext in order to advance through the stack This process ismediated by vesicles The model was strongly supported bythe discovery of COPI and COPII vesicles [182] COPI wereidentified in in vitro assays as being responsible for antero-grade transport between cisterna [107] In these cell-freeexperiments when the formation of COPI was inhibitedanterograde was blocked [183 184] On the other hand itwas clearly demonstrated that COPII vesicles are involved inER exit and transport to the GC [87] Soon it was assumedthat COPII and COPI vesicles act sequentially in the earlysecretory pathway that is ER-to-Golgi and intra-Golgitransport respectively However new experimental data castdoubt on the model First of all a clear role of COPI vesiclesin retrograde transport was demonstrated [120 185] To fitthese data with the model it was postulated that there weretwo types of COPI vesicles involved in anterograde and retro-grade transport at the Golgi stack [186] ldquoPercolatingrdquo COPIvesiclesmaymove bidirectionally up and down in the stack ina random way but allowing a net rate of flow of anterogradecargo in the cis-to-trans direction [187] However immuno-cytochemical [188] and proteomic [9] analysis of thesevesicles showed that they are mostly devoid of anterogradetransport markers Thus the role of COPI vesicles remainscontroversial [189] The small number of Golgi-associatedSNARE and Rab proteins also argues against multiple fusionevents between vesicles and every cisterna in the stacks Oneproblem is that this model does not explain the transport oflarge cargo such as procollagen (300 nm rigid rod) [190] oralgal scales (up to 15ndash2 120583m) [191] within 50ndash60 nm vesiclesInterestingly scales which are electron dense and can beeasily visualized are not observed within vesicles The exis-tence of megavesicles transporting large (gt400 nm) proteinaggregates has been described in an artificial system [192]but it is not clear that this a general mechanism used bynonmodified cells [190]

62 Cisternal Maturation Model This model was postu-lated in the early epoque of electron microscopy [193] andupdated as cisternal progression-maturation model [190194] According to this model cisternae are formed at thecis side of the GC by fusion of ER-derived membranes andthen these newly formed membranes move from the cis to

8 ISRN Cell Biology

Tubules Retrograde COPI vesicles

Cisternal maturation

Anterograde COPI vesicles

Retrograde COPI vesicles

Vesicular transport

Tubules

(a)

(b)

(c)

(d)

Figure 3 Putative role of COPI-coated vesicles and tubules according to vesicular transport and cisternal maturation models for intra-Golgitransport According to vesicular transport model cisternae are static Anterograde transport may be mediated by COPI-coated vesicles andtubular cisternal connections Another type of COPI-coated vesicles mediates retrograde transport (ie the retrieval of proteins that haveescaped from the endoplasmic reticulum) According to cisternal maturation model cisternae move from cis (a) to trans Golgi sides (d)COPI-coated vesicles and transient tubules may be involved in the recycling of Golgi resident proteins (retrograde transport)

the trans side where they become post-Golgi carriers Thusnewly formed cisterna gradually displaces older cisternaetowards the trans side In this model it is not necessary forthe cargo to leave the cisterna and the whole cisterna is takento act as a carrier This model explains the transport of largecargo and an analysis of procollagen transport fits this modelvery well [190] These large molecules are detected in largedistensions at the lateral edge of the cisterna in their transitthrough the stack These distensions are always connected

to the cisterna so that procollagen is not transported bylarge vesicles In contrast the model does not explain thepolarity of the stack and what happens with resident enzymeswhen cisternae disappear at the trans side To overcomethese problems it was assumed that Golgi resident enzymesare packed into COPI vesicles during cisternal progressionand transported backwards Thus Golgi enzymes are notlost but recycled in a trans-to-cis direction maintainingthe polarity of this organelle [195] The cisternae mature by

ISRN Cell Biology 9

acquiring and then losing specific Golgi-resident proteinsThe presence of Golgi resident enzymes in COPI vesicles hasbeen demonstrated [188] although their relative concentra-tion is controversial Life cell imaging studies in yeast stronglysupport this model In Saccharomyces cerevisiae the Golgiis not stacked so that individual cisterna can be analyzedseparately Using cis and trans Golgi markers it was directlydemonstrated that cisternae mature (ie the apparentlyconversion of one type of cisterna into another) [196 197]The cisternal maturation model seems to be more efficientgiven that it would seem easier to transport anterograde cargousing a large carrier (the cisterna) than to use many smallvesicles between adjacent cisternae and repeating this processseveral times until reaching the TGN It is also intuitive thatperi-Golgi vesicles should be restricted to more selective andsmaller trafficking the retrograde pathway

63 Alternative Models Given that none of these modelscompletely explains all the experimental data new modelshave been postulated although some of them are variationsof the two main models

Dual transport model one possibility is that these twomodels are not mutually exclusive but rather complementaryand working simultaneously [198] Cisternae may moveslowly whereas vesicles transport anterograde and retrogradecargo more rapidly Large molecules may use the cisternalmaturation mechanism while small molecules can be trans-ported using vesicular transport [186 198]

Rapid partitioning model This model is based on therapid partitioning of transmembrane cargo and residentenzymes between two lipid phases According to this modelthe GC works as a single compartment but contains pro-cessing and export domains [199] When the cargo reachesthe Golgi it associates with these domains and then leavesthe compartment from every level Again this model hasdifficulty in explaining the polarity of the cisternae and doesnot help visualize the Golgi stack as a single compartment

Kiss-and-runmodelThis model is based onmechanismsoperating in other systems such as endosomes and lysosomesThismodel proposes that two cisternaemay fuse to each otherthrough narrow tubules connecting their lumens transientlyand allowing the transit of cargo before separating [200] Inthis model anterograde transport and retrograde transportoccur simultaneously and a specific retrograde pathway is notnecessary This model may explain several aspects of Golgitransport including the transport of large molecules How-ever some assumptions of the model need to be confirmed(ig machinery and mechanisms for the fusion and fission ofconnections) It is also not clear how all the experimental dataabout the role of COPI coats in retrograde transport fit thismodel

Intra-Golgi transportmediated by tubulesThe absence ofcargo in COPI vesicles suggests that other transport interme-diates such as tubules may operate at the GC As mentionedabove tubules are a common structure surrounding the stackTubules may be involved in the anterograde movement ofcargo through this organelleThe ER and all cisternae may bedirectly connected by tubules and cargo might move along

the secretory pathway like food through the gut [201] Infact conditions that stimulated protein secretion increasethe number of tubular connections between cisternae [136137] Conversely tubules may establish transient connectionsbetween compartments helping COPI vesicles to transportGolgi enzymes retrogradely as indicated by the cisternalmaturation model [46] (Figure 3) Cisternal maturation inyeast occurs although slowly without COPI vesicles suggest-ing that tubules may replace them [197] Low temperature-induced Golgi tubules are enriched in Golgi enzymes andSNARE and Rab proteins involved in intra-Golgi transportwhereas they exclude other proteins associated with ER-Golgi transport [139] Whether the tubules found in thismodel are representative of the carriers involved in intra-Golgi transport remains to be established

7 Concluding Remarks

A century after the discovery of the ldquoapparato reticolareinternordquo [202] it is clear that no model for intra-Golgi trans-port explains all the experimental data But it is also true thatthe ldquohigh polarityrdquo that exits the field has stimulated intenseresearch Recently developed high-resolution methodologiesmay give important clues in this respect Of special interestis the analysis of the structure and composition of tubularand vesicular carriers High-resolution immunocytochemi-cal techniques in combination with electron tomography aswell as proteomic analysis of highly purified samples maysolve the problem or at least definitively reject some modelsIn the end it is possible that each cell type depending of itsspecial characteristics uses a givenmechanism of intra-Golgitransport It also remains possible that a single cell usesdifferent mechanisms of intra-Golgi transport depending onthe amount and type of cargo or its physiological statusMeanwhile cisternal maturation in combination with tubulartransient connections is a very attractive and intuitive modelthat seems to fit most experimental data

Acknowledgments

The work in this paper was supported by Grants fromthe Ministerio de Ciencia e Innovacion (Spain) ConsoliderCOAT (CSD2009-00016) and Fundacion Seneca de la Comu-nidadAutonoma de la Region deMurcia (04542GERM06)

References

[1] G Palade ldquoIntracellular aspects of the process of protein syn-thesisrdquo Science vol 189 no 4200 pp 347ndash358 1975

[2] W Nickel and C Rabouille ldquoMechanisms of regulated uncon-ventional protein secretionrdquo Nature Reviews Molecular CellBiology vol 10 no 2 pp 148ndash155 2009

[3] M G Farquhar and G E Palade ldquoThe Golgi apparatus (com-plex) (1954ndash1981) from artifact to center stagerdquo Journal of CellBiology vol 91 no 3 pp 77sndash103s 1981

[4] M G Farquhar and G E Palade ldquoThe Golgi apparatus 100years of progress and controversyrdquo Trends in Cell Biology vol8 no 1 pp 2ndash10 1998

10 ISRN Cell Biology

[5] C Wilson R Venditti L R Rega A Colanzi G DrsquoAngeloandM A De ldquoThe Golgi apparatus an organelle with multiplecomplex functionsrdquo Biochemical Journal vol 433 no 1 pp 1ndash92011

[6] J Lippincott-Schwartz E Snapp and A Kemvorthy ldquoStudyingprotein dynamics in living cellsrdquoNature Reviews Molecular CellBiology vol 2 no 6 pp 444ndash456 2001

[7] G Perinetti T Muller A Spaar R Polishchuk A Luini andA Egner ldquoCorrelation of 4Pi and electron microscopy to studytransport through single golgi stacks in living cells with superresolutionrdquo Traffic vol 10 no 4 pp 379ndash391 2009

[8] J Lippincott-Schwartz ldquoEmerging in vivo analyses of cellfunction using fluorescence imagingrdquo Annual Review of Bio-chemistry vol 80 pp 327ndash332 2011

[9] A Gilchrist C E Au J Hiding et al ldquoQuantitative proteomicsanalysis of the secretory pathwayrdquo Cell vol 127 no 6 pp 1265ndash1281 2006

[10] J Gannon J J Bergeron and T Nilsson ldquoGolgi and relatedvesicle proteomics simplify to identifyrdquo Cold Spring HarborPerspectives in Biology vol 3 no 12 2011

[11] F Bard L Casano A Mallabiabarrena et al ldquoFunctionalgenomics reveals genes involved in protein secretion and Golgiorganizationrdquo Nature vol 439 pp 604ndash607 2006

[12] J W Slot and H J Geuze ldquoImmunoelectron microscopicexploration of theGolgi complexrdquo Journal ofHistochemistry andCytochemistry vol 31 no 8 pp 1049ndash1056 1983

[13] D ZeuschnerW J C Geerts E vanDonselaar et al ldquoImmuno-electron tomography of ER exit sites reveals the existence of freeCOPII-coated transport carriersrdquoNature Cell Biology vol 8 no4 pp 377ndash383 2006

[14] R S Polishchuk E V Polishchuk P Marra et al ldquoCorrelativelight-electron microscopy reveals the tubular-saccular ultra-structure of carriers operating between Golgi apparatus andplasma membranerdquo Journal of Cell Biology vol 148 no 1 pp45ndash58 2000

[15] B S Donohoe S Mogelsvang and L A Staehelin ldquoElectrontomography of ER Golgi and related membrane systemsrdquoMethods vol 39 no 2 pp 154ndash162 2006

[16] N K Gonatas A Stieber and J O Gonatas ldquoFragmentationof the Golgi apparatus in neurodegenerative diseases and celldeathrdquo Journal of the Neurological Sciences vol 246 no 1-2 pp21ndash30 2006

[17] M C Derby and P A Gleeson ldquoNew insights into membranetrafficking and protein sortingrdquo International Review of Cytol-ogy vol 261 pp 47ndash116 2007

[18] A A Mironov and M Pavelka The Golgi Apparatus State ofthe Art 110 Years after Camillo Golgirsquos Discovery Springer WienNewYork NY USA 2008

[19] E Papanikou and B S Glick ldquoThe yeast Golgi apparatusinsights and mysteriesrdquo FEBS Letters vol 583 no 23 pp 3746ndash3751 2009

[20] J H Wei and J Seemann ldquoMitotic division of the mammalianGolgi apparatusrdquo Seminars in Cell and Developmental Biologyvol 20 no 7 pp 810ndash816 2009

[21] M Anitei and B Hoflack ldquoExit from the trans-Golgi networkfrom molecules to mechanismsrdquo Current Opinion in Cell Biol-ogy vol 23 no 4 pp 443ndash451 2011

[22] J Klumperman ldquoArchitecture of the mammalian Golgirdquo ColdSpring Harbor Perspectives in Biology vol 3 no 7 Article IDa005181 2011

[23] YWang and J Seemann ldquoGolgi biogenesisrdquoCold Spring HarborPerspectives in Biology vol 3 no 10 Article ID a005330 2011

[24] K W Moremen M Tiemeyer and A V Nairn ldquoVertebrateprotein glycosylation diversity synthesis and functionrdquoNatureReviews Molecular Cell Biology vol 13 pp 448ndash462 2012

[25] A J Dalton and M D Felix ldquoA comparative study of the Golgicomplexrdquo The Journal of Biophysical and Biochemical Cytologyvol 2 no 4 pp 79ndash84 1956

[26] A Rambourg Y Clermont and A Marraud ldquoThree dimen-sional structure of the osmium impregnated Golgi apparatus asseen in the high voltage electronmicroscoperdquoAmerican Journalof Anatomy vol 140 no 1 pp 27ndash46 1974

[27] A Rambourg Y Clermont and L Hermo ldquoThree-dimensionalarchitecture of the Golgi apparatus in Sertoli cells of the ratrdquoAmerican Journal of Anatomy vol 154 no 4 pp 455ndash476 1979

[28] M S Ladinsky D NMastronarde J RMcIntosh K E Howelland L A Staehelin ldquoGolgi structure in three dimensionsfunctional insights from the normal rat kidney cellrdquo Journal ofCell Biology vol 144 no 6 pp 1135ndash1149 1999

[29] R S Taylor S M Jones R H Dahl M H Nordeen andK E Howell ldquoCharacterization of the Golgi complex clearedof proteins in transit and examination of calcium uptakeactivitiesrdquo Molecular Biology of the Cell vol 8 no 10 pp 1911ndash1931 1997

[30] MMWuM Grabe S Adams R Y Tsien H P HMoore andT E Machen ldquoMechanisms of pH regulation in the regulatedsecretory pathwayrdquo Journal of Biological Chemistry vol 276 no35 pp 33027ndash33035 2001

[31] J HWei and J Seemann ldquoUnraveling theGolgi ribbonrdquoTrafficvol 11 no 11 pp 1391ndash1400 2010

[32] A A Mironov and G V Beznoussenko ldquoMolecular mecha-nisms responsible for formation of Golgi ribbonrdquoHistology andHistopathology vol 26 no 1 pp 117ndash133 2011

[33] B Storrie JWhite S Rottger E H K Stelzer T Suganuma andT Nilsson ldquoRecycling of Golgi-resident glycosyltransferasesthrough the ER reveals a novel pathway and provides anexplanation for nocodazole-induced Golgi scatteringrdquo Journalof Cell Biology vol 143 no 6 pp 1505ndash1521 1998

[34] J Fan Z Hu L Zeng et al ldquoGolgi apparatus and neurode-generative diseasesrdquo International Journal of DevelopmentalNeuroscience vol 26 no 6 pp 523ndash534 2008

[35] Y Fujita EOhamaMTakatama S Al-Sarraj andKOkamotoldquoFragmentation of Golgi apparatus of nigral neurons with120572-synuclein-positive inclusions in patients with Parkinsonrsquosdiseaserdquo Acta Neuropathologica vol 112 no 3 pp 261ndash2652006

[36] G Thorne-Tjomsland M Dumontier and J C Jamiesonldquo3D topography of noncompact zone Golgi tubules in ratspermatids a computer-assisted serial section reconstructionstudyrdquoThe Anatomical Record vol 250 pp 381ndash396 1998

[37] A S Opat C Van Vliet and P A Gleeson ldquoTrafficking andlocalisation of residentGolgi glycosylation enzymesrdquoBiochimievol 83 no 8 pp 763ndash773 2001

[38] M G Farquhar and H P Hauri ldquoProtein sorting and vesiculartraffic in the Golgi apparatusrdquo inTheGolgi Apparatus E Bergerand J Roth Eds pp 63ndash128 Birkhauser Basel Switzerland1997

[39] G van Meer ldquoLipids of the Golgi membranerdquo Trends in CellBiology vol 8 no 1 pp 29ndash33 1998

[40] J C M Holthuis T Pomorski R J Raggers H Sprong andG Van Meer ldquoThe organizing potential of sphingolipids in

ISRN Cell Biology 11

intracellular membrane transportrdquo Physiological Reviews vol81 no 4 pp 1689ndash1723 2001

[41] D K Banfield ldquoMechanisms of protein retention in the GolgirdquoCold Spring Harbor Perspectives in Biology vol 3 Article IDa005264 2011

[42] D J Gill J Chia J Senewiratne and F Bard ldquoRegulation ofO-glycosylation through Golgi-to-ER relocation of initiationenzymesrdquo Journal of Cell Biology vol 189 no 5 pp 843ndash8582010

[43] A Sesso F Paulo de Faria E S M Iwamura and H Correa ldquoAthree-dimensional reconstruction study of the rough ER-Golgiinterface in serial thin sections of the pancreatic acinar cell ofthe ratrdquo Journal of Cell Science vol 107 no 3 pp 517ndash528 1994

[44] Y Clermont A Rambourg and L Hermo ldquoConnectionsbetween the various elements of the cis- and mid-compart-ments of the Golgi apparatus of early rat spermatidsrdquo Anatomi-cal Record vol 240 no 4 pp 469ndash480 1994

[45] A Rambourg and Y Clermont ldquoThree-dimensional structureof the Golgi apparatus in mammalian cellsrdquo in The GolgiApparatus E G Berger and J Roth Eds pp 37ndash61 BirkhauserBasel Switzerland 1997

[46] G Vivero-Salmeron J Ballesta and J A Martınez-MenarguezldquoHeterotypic tubular connections at the endoplasmic reticu-lum-Golgi complex interfacerdquo Histochemistry and Cell Biologyvol 130 pp 709ndash717 2008

[47] C vanVliet E CThomas AMerino-Trigo R D Teasdale andP A Gleeson ldquoIntracellular sorting and transport of proteinsrdquoProgress in Biophysics and Molecular Biology vol 83 no 1 pp1ndash45 2003

[48] G Griffiths S Pfeiffer K Simons and K Matlin ldquoExit of newlysynthesized membrane proteins from the trans cisterna of theGolgi complex to the plasmamembranerdquo Journal of Cell Biologyvol 101 no 3 pp 949ndash964 1985

[49] G Griffiths S D Fuller R BackMHollinshead S Pfeiffer andK Simons ldquoThe dynamic nature of the Golgi complexrdquo Journalof Cell Biology vol 108 no 2 pp 277ndash297 1989

[50] H J Geuze and D J Morre ldquoTrans-Golgi reticulumrdquo Journal ofElectron Microscopy Technique vol 17 no 1 pp 24ndash34 1991

[51] Y Clermont A Rambourg and L Hermo ldquoTrans-Golgi net-work (TGN) of different cell types three-dimensional structuralcharacteristics and variabilityrdquo Anatomical Record vol 242 no3 pp 289ndash301 1995

[52] R S Polishchuk andA AMironov ldquoStructural aspects of Golgifunctionrdquo Cellular andMolecular Life Sciences vol 61 no 2 pp146ndash158 2004

[53] P A Gleeson J G Lock M R Luke and J L Stow ldquoDomainsof the TGN coats tethers and G proteinsrdquo Traffic vol 5 no 5pp 315ndash326 2004

[54] F Bard and V Malhotra ldquoThe formation of TGN-to-plasma-membrane transport carriersrdquo Annual Review of Cell andDevelopmental Biology vol 22 pp 439ndash455 2006

[55] R D Klausner J G Donaldson and J Lippincott-SchwartzldquoBrefeldin A insights into the control of membrane traffic andorganelle structurerdquo Journal of Cell Biology vol 116 no 5 pp1071ndash1080 1992

[56] J Llopis J M McCaffery A Miyawaki M G Farquhar andR Y Tsien ldquoMeasurement of cytosolic mitochondrial andGolgi pH in single living cells with green fluorescent proteinsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 12 pp 6803ndash6808 1998

[57] H HMollenhauer andD J Morre ldquoThe tubular network of theGolgi apparatusrdquo Histochemistry and Cell Biology vol 109 no5-6 pp 533ndash543 1998

[58] L Orci A Perrelet and J E Rothman ldquoVesicles on stringsMorphological evidence for processive transport within theGolgi stackrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 95 no 5 pp 2279ndash2283 1998

[59] Y Xiang and Y Wang ldquoNew components of the Golgi matrixrdquoCell and Tissue Research vol 344 no 3 pp 365ndash379 2011

[60] N Nakamura C Rabouille R Watson et al ldquoCharacterizationof a cis-Golgi matrix protein GM130rdquo Journal of Cell Biologyvol 131 no 6 pp 1715ndash1726 1995

[61] P Slusarewicz T Nilsson N Hui R Watson and G WarrenldquoIsolation of amatrix that bindsmedial Golgi enzymesrdquo Journalof Cell Biology vol 124 no 4 pp 405ndash413 1994

[62] G Egea and R M Rios ldquoThe role of the cytoskeleton in thestructure and function of the Golgi apparatusrdquo in The GolgiApparatus A A Mironov and M Pavelka Eds pp 270ndash300Springer NewYork NY USA 2008

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[64] R M Rios and M Bornens ldquoThe Golgi apparatus at the cellcentrerdquoCurrent Opinion in Cell Biology vol 15 pp 60ndash66 2003

[65] S Yadav and A D Linstedt ldquoGolgi positioningrdquo Cold SpringHarbor Perspectives in Biology vol 3 pp 1ndash17 2011

[66] J K Burkhardt ldquoThe role of microtubule-based motor proteinsin maintaining the structure and function of the Golgi com-plexrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp 113ndash126 1998

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[68] S Rivero J Cardenas M Bornens and R M Rios ldquoMicro-tubule nucleation at the cis-side of the golgi apparatus requiresAKAP450 and GM130rdquo The EMBO Journal vol 28 no 8 pp1016ndash1028 2009

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[70] P M Miller A W Folkmann A R R Maia N EfimovaA Efimov and I Kaverina ldquoGolgi-derived CLASP-dependentmicrotubules control Golgi organization and polarized traffick-ing in motile cellsrdquo Nature Cell Biology vol 11 no 9 pp 1069ndash1080 2009

[71] F Valderrama A Luna T Babia et al ldquoThe Golgi-associatedCOPI-coated buds and vesicles contain 120573120574-actinrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 97 no 4 pp 1560ndash1565 2000

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[74] F Valderrama J M Duran T Babia H Barth J Renau-Piqueras and G Egea ldquoActin microfilaments facilitate theretrogade transport from the Golgi complex to the endoplasmicreticulum in mammalian cellsrdquo Traffic vol 2 no 10 pp 717ndash726 2001

12 ISRN Cell Biology

[75] A Disanza and G Scita ldquoCytoskeletal regulation coordinatingactin and microtubule dynamics in membrane traffickingrdquoCurrent Biology vol 18 no 18 pp R873ndashR875 2008

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[77] Q T Shen P P Hsiue C V Sindelar M D Welch KG Campellone and H W Wang ldquoStructural insights intoWHAMM-mediated cytoskeletal coordination during mem-brane remodelingrdquoThe Journal of Cell Biology vol 199 pp 111ndash124 2012

[78] T F Roth and K R Porter ldquoYolk protein uptake in the oocyteof the mosquito Aedes aegypti Lrdquo The Journal of Cell Biologyvol 20 pp 313ndash332 1964

[79] B M F Pearse ldquoClathrin a unique protein associated withintracellular transfer of membrane by coated vesiclesrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 73 no 4 pp 1255ndash1259 1976

[80] A Oprins R Duden T E Kreis H J Geuze and J W Slotldquo120573-COP localizes mainly to the cis-Golgi side in exocrinepancreasrdquo Journal of Cell Biology vol 121 no 1 pp 49ndash60 1993

[81] B M F Pearse and M S Robinson ldquoClathrin adaptors andsortingrdquo Annual Review of Cell Biology vol 6 pp 151ndash171 1990

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[83] T Kirchhausen ldquoClathrinrdquo Annual Review of Biochemistry vol69 pp 699ndash727 2000

[84] E Rodriguez-Boulan and A Musch ldquoProtein sorting in theGolgi complex shifting paradigmsrdquo Biochimica et BiophysicaActa vol 1744 no 3 pp 455ndash464 2005

[85] M A McNiven H Cao K R Pitts and Y Yoon ldquoThe dynaminfamily of mechanoenzymes pinching in new placesrdquo Trends inBiochemical Sciences vol 25 no 3 pp 115ndash120 2000

[86] E Eisenberg and L E Greene ldquoMultiple roles of auxilin andHsc70 in clathrin-mediated endocytosisrdquo Traffic vol 8 no 6pp 640ndash646 2007

[87] C Barlowe L Orci T Yeung et al ldquoCOPII a membrane coatformed by sec proteins that drive vesicle budding from theendoplasmic reticulumrdquo Cell vol 77 no 6 pp 895ndash907 1994

[88] L C Bickford E Mossessova and J Goldberg ldquoA structuralview of the COPII vesicle coatrdquo Current Opinion in StructuralBiology vol 14 no 2 pp 147ndash153 2004

[89] D Jensen and R Schekman ldquoCOPII-mediated vesicle forma-tion at a glancerdquo Journal of Cell Science vol 124 no 1 pp 1ndash42011

[90] T Kirchhausen ldquoMaking COPII coatsrdquo Cell vol 129 no 7 pp1251ndash1252 2007

[91] C Barlowe ldquoCOPII and selective export from the endoplasmicreticulumrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp67ndash76 1998

[92] J A Martınez-Menarguez H J Geuze J W Slot and JKlumperman ldquoVesicular tubular clusters between the ER andGolgi mediate concentration of soluble secretory proteins byexclusion fromCOPI-coated vesiclesrdquoCell vol 98 no 1 pp 81ndash90 1999

[93] K Saito M Chen F Bard et al ldquoTANGO1 facilitates cargoloading at endoplasmic reticulum exit sitesrdquo Cell vol 136 no5 pp 891ndash902 2009

[94] L Jin K B Pahuja K E Wickliffe et al ldquoUbiquitin-dependentregulation of COPII coat size and functionrdquo Nature vol 482pp 495ndash500 2012

[95] H P Hauri and A Schweizer ldquoThe endoplasmic reticulum-Golgi intermediate compartmentrdquo Current Opinion in CellBiology vol 4 no 4 pp 600ndash608 1992

[96] S I Bannykh T Rowe and W E Balch ldquoThe organizationof endoplasmic reticulum export complexesrdquo Journal of CellBiology vol 135 no 1 pp 19ndash35 1996

[97] J Saraste and E Kuismanen ldquoPre- and post-Golgi vacuolesoperate in the transport of Semliki Forest virus membraneglycoproteins to the cell surfacerdquo Cell vol 38 no 2 pp 535ndash549 1984

[98] A Schweizer J A M Fransen K Matter T E Kreis L GinselandH PHauri ldquoIdentification of an intermediate compartmentinvolved in protein transport from endoplasmic reticulum toGolgi apparatusrdquo European Journal of Cell Biology vol 53 no 2pp 185ndash196 1990

[99] H Ben-Takaya K Miura R Pepperkok and H P Hauri ldquoLiveimaging of bidirectional traffic from the ERGICrdquo Journal of CellScience vol 118 no 2 pp 357ndash367 2005

[100] Y C Zhang Y Zhou C Z Yang and D S Xiong ldquoA reviewof ERGIC-53 its structure functions regulation and relationswith diseasesrdquo Histology and Histopathology vol 24 no 9 pp1193ndash1204 2009

[101] J F Presley N B Cole T A Schroer K Hirschberg K JM Zaal and J Lippincott-Schwartz ldquoER-to-Golgi transportvisualized in living cellsrdquo Nature vol 389 no 6646 pp 81ndash851997

[102] J A Martınez-Menarguez H J Geuze and J Ballesta ldquoIdenti-fication of two types of beta-COP vesicles in the Golgi complexof rat spermatidsrdquo European Journal of Cell Biology vol 71 pp137ndash143 1996

[103] J Lippincott-Schwartz J G Donaldson A Schweizer et alldquoMicrotubule-dependent retrograde transport of proteins intothe ER in the presence of brefeldin A suggests an ER recyclingpathwayrdquo Cell vol 60 no 5 pp 821ndash836 1990

[104] A Girod B Storrie J C Simpson et al ldquoEvidence for a COP-I-independent transport route from the Golgi complex to theendoplasmic reticulumrdquo Nature Cell Biology vol 1 no 7 pp423ndash430 1999

[105] V Popoff F Adolf B Brugger and F Wieland ldquoCOPI buddingwithin the Golgi stackrdquo Cold Spring Harbor Perspectives inBiology vol 3 Article ID a005231 2011

[106] J Moelleken J Malsam M J Betts et al ldquoDifferential localiza-tion of coatomer complex isoforms within the Golgi apparatusrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 104 no 11 pp 4425ndash4430 2007

[107] L Orci B S Glick and J E Rothman ldquoA new type of coatedvesicular carrier that appears not to contain clathrin its possiblerole in protein transport within theGolgi stackrdquoCell vol 46 no2 pp 171ndash184 1986

[108] V Malhotra T Serafini L Orci J C Shepherd and J ERothman ldquoPurification of a novel class of coated vesiclesmediating biosynthetic protein transport through the Golgistackrdquo Cell vol 58 no 2 pp 329ndash336 1989

[109] M G Waters T Serafini and J E Rothman ldquolsquoCoatomerrsquo acytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesiclesrdquo Nature vol 349 no 6306 pp248ndash251 1991

[110] T Serafini L Orci M Amherdt M Brunner R A Kahn andJ E Rothman ldquoADP-ribosylation factor is a subunit of the coatof Golgi-derived COP-coated vesicles a novel role for a GTP-binding proteinrdquo Cell vol 67 no 2 pp 239ndash253 1991

ISRN Cell Biology 13

[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

[112] K Kawamoto Y Yoshida H Tamaki et al ldquoGBF1 a guaninenucleotide exchange factor for ADP-ribosylation factors islocalized to the cis-Golgi and involved inmembrane associationof the COPI coatrdquo Traffic vol 3 no 7 pp 483ndash495 2002

[113] R Garcıa-Mata T Szul C Alvarez and E Sztul ldquoADP-ribosylation factorCOPI-dependent events at the endoplas-mic reticulum-Golgi interface are regulated by the guaninenucleotide exchange factor GBF1rdquoMolecular Biology of the Cellvol 14 no 6 pp 2250ndash2261 2003

[114] H Inoue and P A Randazzo ldquoArf GAPs and their interactingproteinsrdquo Traffic vol 8 no 11 pp 1465ndash1475 2007

[115] G Tanigawa L Orci M Amherdt M Ravazzola J B Helmsand J E Rothman ldquoHydrolysis of bound GTP by ARF proteintriggers uncoating of Golgi- derived COP-coated vesiclesrdquoJournal of Cell Biology vol 123 no 6 pp 1365ndash1371 1993

[116] Y Shiba and P A Randazzo ldquoArfGAP1 function in COPImediated membrane traffic currently debated models andcomparison to other coat-binding ArfGAPsrdquo Histology andHistopathology vol 27 pp 1143ndash1153 2012

[117] J Bigay P Gounon S Roblneau and B Antonny ldquoLipidpacking sensed by ArfGAP1 couples COPI coat disassembly tomembrane bilayer curvaturerdquo Nature vol 426 no 6966 pp563ndash566 2003

[118] W Nickel J Malsam K Gorgas et al ldquoUptake by COPI-coatedvesicles of both anterograde and retrograde cargo is inhibitedby GTP120574S in vitrordquo Journal of Cell Science vol 111 no 20 pp3081ndash3090 1998

[119] R Beck M Rawet F T Wieland and D Cassel ldquoThe COPIsystemmolecularmechanisms and functionrdquo FEBS Letters vol583 pp 2701ndash2709 2009

[120] F Letourneur E C Gaynor S Hennecke et al ldquoCoatomeris essential for retrieval of dilysine-tagged proteins to theendoplasmic reticulumrdquo Cell vol 79 no 7 pp 1199ndash1207 1994

[121] R Schindler C Itin M Zerial F Lottspeich and H P HaurildquoERGIC-53 a membrane protein of the ER-Golgi intermediatecompartment carries an ER retention motifrdquo European Journalof Cell Biology vol 61 no 1 pp 1ndash9 1993

[122] L P Jackson M Lewis H M Kent et al ldquoMolecular basis forrecognition of dilysine trafficking motifs by COPIrdquo Develop-mental Cell vol 23 pp 1ndash8 2012

[123] W Nickel K Sohn C Bunning and F T Wieland ldquop23 Amajor COPI-vesicle membrane protein constitutively cyclesthrough the early secretory pathwayrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 94 no21 pp 11393ndash11398 1997

[124] J C Semenza K G Hardwick N Dean and H R BPelham ldquoERD2 a yeast gene required for the receptor-mediatedretrieval of luminal ER proteins from the secretory pathwayrdquoCell vol 61 no 7 pp 1349ndash1357 1990

[125] I Majoul M Straub S W Hell R Duden and H D SolingldquoKDEL-cargo regulates interactions between proteins involvedin COPI vesicle traffic measurements in living cells usingFRETrdquo Developmental Cell vol 1 no 1 pp 139ndash153 2001

[126] B S Glick ldquoOrganization of the Golgi apparatusrdquo CurrentOpinion in Cell Biology vol 12 no 4 pp 450ndash456 2000

[127] R Blum D J Stephens and I Schulz ldquoLumenal targeted GFPused as a marker of soluble cargo visualises rapid ERGIC toGolgi traffic by a tubulo-vesicular networkrdquo Journal of CellScience vol 113 no 18 pp 3151ndash3159 2000

[128] J C Simpson T Nilsson and R Pepperkok ldquoBiogenesis oftubular ER-to-golgi transport intermediatesrdquoMolecular Biologyof the Cell vol 17 no 2 pp 723ndash737 2006

[129] K Hirschberg C M Miller J Ellenberg et al ldquoKinetic analysisof secretory protein traffic and characterization of Golgi toplasma membrane transport intermediates in living cellsrdquoJournal of Cell Biology vol 143 no 6 pp 1485ndash1503 1998

[130] D Toomre P Keller JWhite J C Olivo and K Simons ldquoDual-color visualization of trans-Golgi network to plasmamembranetraffic alongmicrotubules in living cellsrdquo Journal of Cell Sciencevol 112 no 1 pp 21ndash33 1999

[131] L Hermo A Rambourg and Y Clermont ldquoThree-dimensionalarchitecture of the cortical region of the Golgi apparatus in ratspermatidsrdquo American Journal of Anatomy vol 157 no 4 pp357ndash373 1980

[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

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BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

ISRN Cell Biology 7

fusion They have recently been classified into three classesoligomeric complexes that work as Rab effectors and bindsSNARE oligomeric complexes that function as GEFs for Rabproteins and finally coiled-coil tethers [177] Proteins withextensive coiled-coil domains are long allowing long distancetethering These bridges not only facilitate the formation ofSNARE complexes but also may provide an initial specificityfor membrane fusionMembers of this family associated withthe Golgi are called golgins [178] In addition to tetheringthey have a role in Golgi stacking and form the Golgi matrixThis family includes p115 and GM130 the first of which isassociated with COPI and COPII vesicles the ERGIC andcis-Golgi membranes This protein is believed to be involvedin tethering of COPII vesicles to ERGIC membranes and thetransport events from these elements to the cis-Golgi It is alsopossible that it participates in transport between cisternaeThe recruitment of p115 to membranes is Rab1 dependentIt also interacts with ER-Golgi SNAREs COG subunits andother coiled-coil proteins such as GM130 and giantin Thesignificance of the last interaction is not clear GM130 isanother coiled-coil protein associated with the cis Golgi Itinteracts with many proteins including GRASP65 p115 Rab1Rab2 Rab33b and sintaxin5 P115 and GM130 are membersof the family of golgins which were first identified as Golgi-localized autoantigens using antibodies derived from thesera of patients with a variety of autoimmune disorders Asindicated above GM130 and p115 are also components ofthe Golgi matrix Apart from their role as tethers togetherwith other members of the golgin family such as GRASP65and giantin they are involved in maintaining the stackedmorphology of the cisterna and the Golgi ribbon [179]

Multisubunit complexes associated with the Golgiinclude Dsl1 COG and TRAPPIII [177] Dsl1 is a three-unitcomplex involved in Golgi-to-ER transport where it acts astethering COPI vesicles It interacts and stabilizes an SNAREcomplex at the ER The conserved oligomeric Golgi (COG)complex formed of 8 subunits (Cog1ndash8) found at the cis- andmedial Golgi cisternae is believed to be involved in transportto the Golgi and intra-Golgi recycling of Golgi resident pro-teins [180] Components of this tethering factor interactwith COPI components SNARE proteins (syntaxin 5) andcoiled-coil tether (p115) and are the effectors of several Rabproteins (Rab1 Rab6) Transport protein particle (TRAPP) isanother multisubunit complex that works as tethering factor[181] Two complexes have been identified TRAPP I andTRAPPII which are involved in entry and exit from theGC tethering COPII and COPI vesicles respectively Theywork as GEF for Rab1 and the activation of this GTPasemight recruit other tethers (as p115 or COG) [177] Howeverthey do not interact directly with SNAREs It is possible thatthere is a cascade of tethering factors that facilitates cargotransport

6 Intra-Golgi Transport

The mode of transport across the GC remains controversialTwo main models have been proposed vesicular transportand cisternal maturation The first one proposes that Golgi

cisternae are static so that the cargo must move via vesiclesThe second model support that cisterna are dynamic struc-tures that move from the cis to trans Golgi sideThus accord-ing to this model the entire cisterna is the carrier In thesemodels COPI-coated vesicles are responsible for antero-grade and retrograde transport respectively (Figure 3) Sinceneither of these models explains all the experimental data acombination of the same models and new models have beenproposed (see below)

61 Vesicular Transport Model This model was launchedby Palade in 1975 and was widely accepted for many yearsbecause it provides a good explanation for the well-knowncompartmentalization of the Golgi resident enzymes In thismodel it is assumed that cisternae are stable compartmentsso that the cargo must leave one cisterna and move to thenext in order to advance through the stack This process ismediated by vesicles The model was strongly supported bythe discovery of COPI and COPII vesicles [182] COPI wereidentified in in vitro assays as being responsible for antero-grade transport between cisterna [107] In these cell-freeexperiments when the formation of COPI was inhibitedanterograde was blocked [183 184] On the other hand itwas clearly demonstrated that COPII vesicles are involved inER exit and transport to the GC [87] Soon it was assumedthat COPII and COPI vesicles act sequentially in the earlysecretory pathway that is ER-to-Golgi and intra-Golgitransport respectively However new experimental data castdoubt on the model First of all a clear role of COPI vesiclesin retrograde transport was demonstrated [120 185] To fitthese data with the model it was postulated that there weretwo types of COPI vesicles involved in anterograde and retro-grade transport at the Golgi stack [186] ldquoPercolatingrdquo COPIvesiclesmaymove bidirectionally up and down in the stack ina random way but allowing a net rate of flow of anterogradecargo in the cis-to-trans direction [187] However immuno-cytochemical [188] and proteomic [9] analysis of thesevesicles showed that they are mostly devoid of anterogradetransport markers Thus the role of COPI vesicles remainscontroversial [189] The small number of Golgi-associatedSNARE and Rab proteins also argues against multiple fusionevents between vesicles and every cisterna in the stacks Oneproblem is that this model does not explain the transport oflarge cargo such as procollagen (300 nm rigid rod) [190] oralgal scales (up to 15ndash2 120583m) [191] within 50ndash60 nm vesiclesInterestingly scales which are electron dense and can beeasily visualized are not observed within vesicles The exis-tence of megavesicles transporting large (gt400 nm) proteinaggregates has been described in an artificial system [192]but it is not clear that this a general mechanism used bynonmodified cells [190]

62 Cisternal Maturation Model This model was postu-lated in the early epoque of electron microscopy [193] andupdated as cisternal progression-maturation model [190194] According to this model cisternae are formed at thecis side of the GC by fusion of ER-derived membranes andthen these newly formed membranes move from the cis to

8 ISRN Cell Biology

Tubules Retrograde COPI vesicles

Cisternal maturation

Anterograde COPI vesicles

Retrograde COPI vesicles

Vesicular transport

Tubules

(a)

(b)

(c)

(d)

Figure 3 Putative role of COPI-coated vesicles and tubules according to vesicular transport and cisternal maturation models for intra-Golgitransport According to vesicular transport model cisternae are static Anterograde transport may be mediated by COPI-coated vesicles andtubular cisternal connections Another type of COPI-coated vesicles mediates retrograde transport (ie the retrieval of proteins that haveescaped from the endoplasmic reticulum) According to cisternal maturation model cisternae move from cis (a) to trans Golgi sides (d)COPI-coated vesicles and transient tubules may be involved in the recycling of Golgi resident proteins (retrograde transport)

the trans side where they become post-Golgi carriers Thusnewly formed cisterna gradually displaces older cisternaetowards the trans side In this model it is not necessary forthe cargo to leave the cisterna and the whole cisterna is takento act as a carrier This model explains the transport of largecargo and an analysis of procollagen transport fits this modelvery well [190] These large molecules are detected in largedistensions at the lateral edge of the cisterna in their transitthrough the stack These distensions are always connected

to the cisterna so that procollagen is not transported bylarge vesicles In contrast the model does not explain thepolarity of the stack and what happens with resident enzymeswhen cisternae disappear at the trans side To overcomethese problems it was assumed that Golgi resident enzymesare packed into COPI vesicles during cisternal progressionand transported backwards Thus Golgi enzymes are notlost but recycled in a trans-to-cis direction maintainingthe polarity of this organelle [195] The cisternae mature by

ISRN Cell Biology 9

acquiring and then losing specific Golgi-resident proteinsThe presence of Golgi resident enzymes in COPI vesicles hasbeen demonstrated [188] although their relative concentra-tion is controversial Life cell imaging studies in yeast stronglysupport this model In Saccharomyces cerevisiae the Golgiis not stacked so that individual cisterna can be analyzedseparately Using cis and trans Golgi markers it was directlydemonstrated that cisternae mature (ie the apparentlyconversion of one type of cisterna into another) [196 197]The cisternal maturation model seems to be more efficientgiven that it would seem easier to transport anterograde cargousing a large carrier (the cisterna) than to use many smallvesicles between adjacent cisternae and repeating this processseveral times until reaching the TGN It is also intuitive thatperi-Golgi vesicles should be restricted to more selective andsmaller trafficking the retrograde pathway

63 Alternative Models Given that none of these modelscompletely explains all the experimental data new modelshave been postulated although some of them are variationsof the two main models

Dual transport model one possibility is that these twomodels are not mutually exclusive but rather complementaryand working simultaneously [198] Cisternae may moveslowly whereas vesicles transport anterograde and retrogradecargo more rapidly Large molecules may use the cisternalmaturation mechanism while small molecules can be trans-ported using vesicular transport [186 198]

Rapid partitioning model This model is based on therapid partitioning of transmembrane cargo and residentenzymes between two lipid phases According to this modelthe GC works as a single compartment but contains pro-cessing and export domains [199] When the cargo reachesthe Golgi it associates with these domains and then leavesthe compartment from every level Again this model hasdifficulty in explaining the polarity of the cisternae and doesnot help visualize the Golgi stack as a single compartment

Kiss-and-runmodelThis model is based onmechanismsoperating in other systems such as endosomes and lysosomesThismodel proposes that two cisternaemay fuse to each otherthrough narrow tubules connecting their lumens transientlyand allowing the transit of cargo before separating [200] Inthis model anterograde transport and retrograde transportoccur simultaneously and a specific retrograde pathway is notnecessary This model may explain several aspects of Golgitransport including the transport of large molecules How-ever some assumptions of the model need to be confirmed(ig machinery and mechanisms for the fusion and fission ofconnections) It is also not clear how all the experimental dataabout the role of COPI coats in retrograde transport fit thismodel

Intra-Golgi transportmediated by tubulesThe absence ofcargo in COPI vesicles suggests that other transport interme-diates such as tubules may operate at the GC As mentionedabove tubules are a common structure surrounding the stackTubules may be involved in the anterograde movement ofcargo through this organelleThe ER and all cisternae may bedirectly connected by tubules and cargo might move along

the secretory pathway like food through the gut [201] Infact conditions that stimulated protein secretion increasethe number of tubular connections between cisternae [136137] Conversely tubules may establish transient connectionsbetween compartments helping COPI vesicles to transportGolgi enzymes retrogradely as indicated by the cisternalmaturation model [46] (Figure 3) Cisternal maturation inyeast occurs although slowly without COPI vesicles suggest-ing that tubules may replace them [197] Low temperature-induced Golgi tubules are enriched in Golgi enzymes andSNARE and Rab proteins involved in intra-Golgi transportwhereas they exclude other proteins associated with ER-Golgi transport [139] Whether the tubules found in thismodel are representative of the carriers involved in intra-Golgi transport remains to be established

7 Concluding Remarks

A century after the discovery of the ldquoapparato reticolareinternordquo [202] it is clear that no model for intra-Golgi trans-port explains all the experimental data But it is also true thatthe ldquohigh polarityrdquo that exits the field has stimulated intenseresearch Recently developed high-resolution methodologiesmay give important clues in this respect Of special interestis the analysis of the structure and composition of tubularand vesicular carriers High-resolution immunocytochemi-cal techniques in combination with electron tomography aswell as proteomic analysis of highly purified samples maysolve the problem or at least definitively reject some modelsIn the end it is possible that each cell type depending of itsspecial characteristics uses a givenmechanism of intra-Golgitransport It also remains possible that a single cell usesdifferent mechanisms of intra-Golgi transport depending onthe amount and type of cargo or its physiological statusMeanwhile cisternal maturation in combination with tubulartransient connections is a very attractive and intuitive modelthat seems to fit most experimental data

Acknowledgments

The work in this paper was supported by Grants fromthe Ministerio de Ciencia e Innovacion (Spain) ConsoliderCOAT (CSD2009-00016) and Fundacion Seneca de la Comu-nidadAutonoma de la Region deMurcia (04542GERM06)

References

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[2] W Nickel and C Rabouille ldquoMechanisms of regulated uncon-ventional protein secretionrdquo Nature Reviews Molecular CellBiology vol 10 no 2 pp 148ndash155 2009

[3] M G Farquhar and G E Palade ldquoThe Golgi apparatus (com-plex) (1954ndash1981) from artifact to center stagerdquo Journal of CellBiology vol 91 no 3 pp 77sndash103s 1981

[4] M G Farquhar and G E Palade ldquoThe Golgi apparatus 100years of progress and controversyrdquo Trends in Cell Biology vol8 no 1 pp 2ndash10 1998

10 ISRN Cell Biology

[5] C Wilson R Venditti L R Rega A Colanzi G DrsquoAngeloandM A De ldquoThe Golgi apparatus an organelle with multiplecomplex functionsrdquo Biochemical Journal vol 433 no 1 pp 1ndash92011

[6] J Lippincott-Schwartz E Snapp and A Kemvorthy ldquoStudyingprotein dynamics in living cellsrdquoNature Reviews Molecular CellBiology vol 2 no 6 pp 444ndash456 2001

[7] G Perinetti T Muller A Spaar R Polishchuk A Luini andA Egner ldquoCorrelation of 4Pi and electron microscopy to studytransport through single golgi stacks in living cells with superresolutionrdquo Traffic vol 10 no 4 pp 379ndash391 2009

[8] J Lippincott-Schwartz ldquoEmerging in vivo analyses of cellfunction using fluorescence imagingrdquo Annual Review of Bio-chemistry vol 80 pp 327ndash332 2011

[9] A Gilchrist C E Au J Hiding et al ldquoQuantitative proteomicsanalysis of the secretory pathwayrdquo Cell vol 127 no 6 pp 1265ndash1281 2006

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[14] R S Polishchuk E V Polishchuk P Marra et al ldquoCorrelativelight-electron microscopy reveals the tubular-saccular ultra-structure of carriers operating between Golgi apparatus andplasma membranerdquo Journal of Cell Biology vol 148 no 1 pp45ndash58 2000

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[21] M Anitei and B Hoflack ldquoExit from the trans-Golgi networkfrom molecules to mechanismsrdquo Current Opinion in Cell Biol-ogy vol 23 no 4 pp 443ndash451 2011

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[23] YWang and J Seemann ldquoGolgi biogenesisrdquoCold Spring HarborPerspectives in Biology vol 3 no 10 Article ID a005330 2011

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[28] M S Ladinsky D NMastronarde J RMcIntosh K E Howelland L A Staehelin ldquoGolgi structure in three dimensionsfunctional insights from the normal rat kidney cellrdquo Journal ofCell Biology vol 144 no 6 pp 1135ndash1149 1999

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ISRN Cell Biology 11

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[52] R S Polishchuk andA AMironov ldquoStructural aspects of Golgifunctionrdquo Cellular andMolecular Life Sciences vol 61 no 2 pp146ndash158 2004

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[54] F Bard and V Malhotra ldquoThe formation of TGN-to-plasma-membrane transport carriersrdquo Annual Review of Cell andDevelopmental Biology vol 22 pp 439ndash455 2006

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[57] H HMollenhauer andD J Morre ldquoThe tubular network of theGolgi apparatusrdquo Histochemistry and Cell Biology vol 109 no5-6 pp 533ndash543 1998

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12 ISRN Cell Biology

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[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

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[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

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BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

8 ISRN Cell Biology

Tubules Retrograde COPI vesicles

Cisternal maturation

Anterograde COPI vesicles

Retrograde COPI vesicles

Vesicular transport

Tubules

(a)

(b)

(c)

(d)

Figure 3 Putative role of COPI-coated vesicles and tubules according to vesicular transport and cisternal maturation models for intra-Golgitransport According to vesicular transport model cisternae are static Anterograde transport may be mediated by COPI-coated vesicles andtubular cisternal connections Another type of COPI-coated vesicles mediates retrograde transport (ie the retrieval of proteins that haveescaped from the endoplasmic reticulum) According to cisternal maturation model cisternae move from cis (a) to trans Golgi sides (d)COPI-coated vesicles and transient tubules may be involved in the recycling of Golgi resident proteins (retrograde transport)

the trans side where they become post-Golgi carriers Thusnewly formed cisterna gradually displaces older cisternaetowards the trans side In this model it is not necessary forthe cargo to leave the cisterna and the whole cisterna is takento act as a carrier This model explains the transport of largecargo and an analysis of procollagen transport fits this modelvery well [190] These large molecules are detected in largedistensions at the lateral edge of the cisterna in their transitthrough the stack These distensions are always connected

to the cisterna so that procollagen is not transported bylarge vesicles In contrast the model does not explain thepolarity of the stack and what happens with resident enzymeswhen cisternae disappear at the trans side To overcomethese problems it was assumed that Golgi resident enzymesare packed into COPI vesicles during cisternal progressionand transported backwards Thus Golgi enzymes are notlost but recycled in a trans-to-cis direction maintainingthe polarity of this organelle [195] The cisternae mature by

ISRN Cell Biology 9

acquiring and then losing specific Golgi-resident proteinsThe presence of Golgi resident enzymes in COPI vesicles hasbeen demonstrated [188] although their relative concentra-tion is controversial Life cell imaging studies in yeast stronglysupport this model In Saccharomyces cerevisiae the Golgiis not stacked so that individual cisterna can be analyzedseparately Using cis and trans Golgi markers it was directlydemonstrated that cisternae mature (ie the apparentlyconversion of one type of cisterna into another) [196 197]The cisternal maturation model seems to be more efficientgiven that it would seem easier to transport anterograde cargousing a large carrier (the cisterna) than to use many smallvesicles between adjacent cisternae and repeating this processseveral times until reaching the TGN It is also intuitive thatperi-Golgi vesicles should be restricted to more selective andsmaller trafficking the retrograde pathway

63 Alternative Models Given that none of these modelscompletely explains all the experimental data new modelshave been postulated although some of them are variationsof the two main models

Dual transport model one possibility is that these twomodels are not mutually exclusive but rather complementaryand working simultaneously [198] Cisternae may moveslowly whereas vesicles transport anterograde and retrogradecargo more rapidly Large molecules may use the cisternalmaturation mechanism while small molecules can be trans-ported using vesicular transport [186 198]

Rapid partitioning model This model is based on therapid partitioning of transmembrane cargo and residentenzymes between two lipid phases According to this modelthe GC works as a single compartment but contains pro-cessing and export domains [199] When the cargo reachesthe Golgi it associates with these domains and then leavesthe compartment from every level Again this model hasdifficulty in explaining the polarity of the cisternae and doesnot help visualize the Golgi stack as a single compartment

Kiss-and-runmodelThis model is based onmechanismsoperating in other systems such as endosomes and lysosomesThismodel proposes that two cisternaemay fuse to each otherthrough narrow tubules connecting their lumens transientlyand allowing the transit of cargo before separating [200] Inthis model anterograde transport and retrograde transportoccur simultaneously and a specific retrograde pathway is notnecessary This model may explain several aspects of Golgitransport including the transport of large molecules How-ever some assumptions of the model need to be confirmed(ig machinery and mechanisms for the fusion and fission ofconnections) It is also not clear how all the experimental dataabout the role of COPI coats in retrograde transport fit thismodel

Intra-Golgi transportmediated by tubulesThe absence ofcargo in COPI vesicles suggests that other transport interme-diates such as tubules may operate at the GC As mentionedabove tubules are a common structure surrounding the stackTubules may be involved in the anterograde movement ofcargo through this organelleThe ER and all cisternae may bedirectly connected by tubules and cargo might move along

the secretory pathway like food through the gut [201] Infact conditions that stimulated protein secretion increasethe number of tubular connections between cisternae [136137] Conversely tubules may establish transient connectionsbetween compartments helping COPI vesicles to transportGolgi enzymes retrogradely as indicated by the cisternalmaturation model [46] (Figure 3) Cisternal maturation inyeast occurs although slowly without COPI vesicles suggest-ing that tubules may replace them [197] Low temperature-induced Golgi tubules are enriched in Golgi enzymes andSNARE and Rab proteins involved in intra-Golgi transportwhereas they exclude other proteins associated with ER-Golgi transport [139] Whether the tubules found in thismodel are representative of the carriers involved in intra-Golgi transport remains to be established

7 Concluding Remarks

A century after the discovery of the ldquoapparato reticolareinternordquo [202] it is clear that no model for intra-Golgi trans-port explains all the experimental data But it is also true thatthe ldquohigh polarityrdquo that exits the field has stimulated intenseresearch Recently developed high-resolution methodologiesmay give important clues in this respect Of special interestis the analysis of the structure and composition of tubularand vesicular carriers High-resolution immunocytochemi-cal techniques in combination with electron tomography aswell as proteomic analysis of highly purified samples maysolve the problem or at least definitively reject some modelsIn the end it is possible that each cell type depending of itsspecial characteristics uses a givenmechanism of intra-Golgitransport It also remains possible that a single cell usesdifferent mechanisms of intra-Golgi transport depending onthe amount and type of cargo or its physiological statusMeanwhile cisternal maturation in combination with tubulartransient connections is a very attractive and intuitive modelthat seems to fit most experimental data

Acknowledgments

The work in this paper was supported by Grants fromthe Ministerio de Ciencia e Innovacion (Spain) ConsoliderCOAT (CSD2009-00016) and Fundacion Seneca de la Comu-nidadAutonoma de la Region deMurcia (04542GERM06)

References

[1] G Palade ldquoIntracellular aspects of the process of protein syn-thesisrdquo Science vol 189 no 4200 pp 347ndash358 1975

[2] W Nickel and C Rabouille ldquoMechanisms of regulated uncon-ventional protein secretionrdquo Nature Reviews Molecular CellBiology vol 10 no 2 pp 148ndash155 2009

[3] M G Farquhar and G E Palade ldquoThe Golgi apparatus (com-plex) (1954ndash1981) from artifact to center stagerdquo Journal of CellBiology vol 91 no 3 pp 77sndash103s 1981

[4] M G Farquhar and G E Palade ldquoThe Golgi apparatus 100years of progress and controversyrdquo Trends in Cell Biology vol8 no 1 pp 2ndash10 1998

10 ISRN Cell Biology

[5] C Wilson R Venditti L R Rega A Colanzi G DrsquoAngeloandM A De ldquoThe Golgi apparatus an organelle with multiplecomplex functionsrdquo Biochemical Journal vol 433 no 1 pp 1ndash92011

[6] J Lippincott-Schwartz E Snapp and A Kemvorthy ldquoStudyingprotein dynamics in living cellsrdquoNature Reviews Molecular CellBiology vol 2 no 6 pp 444ndash456 2001

[7] G Perinetti T Muller A Spaar R Polishchuk A Luini andA Egner ldquoCorrelation of 4Pi and electron microscopy to studytransport through single golgi stacks in living cells with superresolutionrdquo Traffic vol 10 no 4 pp 379ndash391 2009

[8] J Lippincott-Schwartz ldquoEmerging in vivo analyses of cellfunction using fluorescence imagingrdquo Annual Review of Bio-chemistry vol 80 pp 327ndash332 2011

[9] A Gilchrist C E Au J Hiding et al ldquoQuantitative proteomicsanalysis of the secretory pathwayrdquo Cell vol 127 no 6 pp 1265ndash1281 2006

[10] J Gannon J J Bergeron and T Nilsson ldquoGolgi and relatedvesicle proteomics simplify to identifyrdquo Cold Spring HarborPerspectives in Biology vol 3 no 12 2011

[11] F Bard L Casano A Mallabiabarrena et al ldquoFunctionalgenomics reveals genes involved in protein secretion and Golgiorganizationrdquo Nature vol 439 pp 604ndash607 2006

[12] J W Slot and H J Geuze ldquoImmunoelectron microscopicexploration of theGolgi complexrdquo Journal ofHistochemistry andCytochemistry vol 31 no 8 pp 1049ndash1056 1983

[13] D ZeuschnerW J C Geerts E vanDonselaar et al ldquoImmuno-electron tomography of ER exit sites reveals the existence of freeCOPII-coated transport carriersrdquoNature Cell Biology vol 8 no4 pp 377ndash383 2006

[14] R S Polishchuk E V Polishchuk P Marra et al ldquoCorrelativelight-electron microscopy reveals the tubular-saccular ultra-structure of carriers operating between Golgi apparatus andplasma membranerdquo Journal of Cell Biology vol 148 no 1 pp45ndash58 2000

[15] B S Donohoe S Mogelsvang and L A Staehelin ldquoElectrontomography of ER Golgi and related membrane systemsrdquoMethods vol 39 no 2 pp 154ndash162 2006

[16] N K Gonatas A Stieber and J O Gonatas ldquoFragmentationof the Golgi apparatus in neurodegenerative diseases and celldeathrdquo Journal of the Neurological Sciences vol 246 no 1-2 pp21ndash30 2006

[17] M C Derby and P A Gleeson ldquoNew insights into membranetrafficking and protein sortingrdquo International Review of Cytol-ogy vol 261 pp 47ndash116 2007

[18] A A Mironov and M Pavelka The Golgi Apparatus State ofthe Art 110 Years after Camillo Golgirsquos Discovery Springer WienNewYork NY USA 2008

[19] E Papanikou and B S Glick ldquoThe yeast Golgi apparatusinsights and mysteriesrdquo FEBS Letters vol 583 no 23 pp 3746ndash3751 2009

[20] J H Wei and J Seemann ldquoMitotic division of the mammalianGolgi apparatusrdquo Seminars in Cell and Developmental Biologyvol 20 no 7 pp 810ndash816 2009

[21] M Anitei and B Hoflack ldquoExit from the trans-Golgi networkfrom molecules to mechanismsrdquo Current Opinion in Cell Biol-ogy vol 23 no 4 pp 443ndash451 2011

[22] J Klumperman ldquoArchitecture of the mammalian Golgirdquo ColdSpring Harbor Perspectives in Biology vol 3 no 7 Article IDa005181 2011

[23] YWang and J Seemann ldquoGolgi biogenesisrdquoCold Spring HarborPerspectives in Biology vol 3 no 10 Article ID a005330 2011

[24] K W Moremen M Tiemeyer and A V Nairn ldquoVertebrateprotein glycosylation diversity synthesis and functionrdquoNatureReviews Molecular Cell Biology vol 13 pp 448ndash462 2012

[25] A J Dalton and M D Felix ldquoA comparative study of the Golgicomplexrdquo The Journal of Biophysical and Biochemical Cytologyvol 2 no 4 pp 79ndash84 1956

[26] A Rambourg Y Clermont and A Marraud ldquoThree dimen-sional structure of the osmium impregnated Golgi apparatus asseen in the high voltage electronmicroscoperdquoAmerican Journalof Anatomy vol 140 no 1 pp 27ndash46 1974

[27] A Rambourg Y Clermont and L Hermo ldquoThree-dimensionalarchitecture of the Golgi apparatus in Sertoli cells of the ratrdquoAmerican Journal of Anatomy vol 154 no 4 pp 455ndash476 1979

[28] M S Ladinsky D NMastronarde J RMcIntosh K E Howelland L A Staehelin ldquoGolgi structure in three dimensionsfunctional insights from the normal rat kidney cellrdquo Journal ofCell Biology vol 144 no 6 pp 1135ndash1149 1999

[29] R S Taylor S M Jones R H Dahl M H Nordeen andK E Howell ldquoCharacterization of the Golgi complex clearedof proteins in transit and examination of calcium uptakeactivitiesrdquo Molecular Biology of the Cell vol 8 no 10 pp 1911ndash1931 1997

[30] MMWuM Grabe S Adams R Y Tsien H P HMoore andT E Machen ldquoMechanisms of pH regulation in the regulatedsecretory pathwayrdquo Journal of Biological Chemistry vol 276 no35 pp 33027ndash33035 2001

[31] J HWei and J Seemann ldquoUnraveling theGolgi ribbonrdquoTrafficvol 11 no 11 pp 1391ndash1400 2010

[32] A A Mironov and G V Beznoussenko ldquoMolecular mecha-nisms responsible for formation of Golgi ribbonrdquoHistology andHistopathology vol 26 no 1 pp 117ndash133 2011

[33] B Storrie JWhite S Rottger E H K Stelzer T Suganuma andT Nilsson ldquoRecycling of Golgi-resident glycosyltransferasesthrough the ER reveals a novel pathway and provides anexplanation for nocodazole-induced Golgi scatteringrdquo Journalof Cell Biology vol 143 no 6 pp 1505ndash1521 1998

[34] J Fan Z Hu L Zeng et al ldquoGolgi apparatus and neurode-generative diseasesrdquo International Journal of DevelopmentalNeuroscience vol 26 no 6 pp 523ndash534 2008

[35] Y Fujita EOhamaMTakatama S Al-Sarraj andKOkamotoldquoFragmentation of Golgi apparatus of nigral neurons with120572-synuclein-positive inclusions in patients with Parkinsonrsquosdiseaserdquo Acta Neuropathologica vol 112 no 3 pp 261ndash2652006

[36] G Thorne-Tjomsland M Dumontier and J C Jamiesonldquo3D topography of noncompact zone Golgi tubules in ratspermatids a computer-assisted serial section reconstructionstudyrdquoThe Anatomical Record vol 250 pp 381ndash396 1998

[37] A S Opat C Van Vliet and P A Gleeson ldquoTrafficking andlocalisation of residentGolgi glycosylation enzymesrdquoBiochimievol 83 no 8 pp 763ndash773 2001

[38] M G Farquhar and H P Hauri ldquoProtein sorting and vesiculartraffic in the Golgi apparatusrdquo inTheGolgi Apparatus E Bergerand J Roth Eds pp 63ndash128 Birkhauser Basel Switzerland1997

[39] G van Meer ldquoLipids of the Golgi membranerdquo Trends in CellBiology vol 8 no 1 pp 29ndash33 1998

[40] J C M Holthuis T Pomorski R J Raggers H Sprong andG Van Meer ldquoThe organizing potential of sphingolipids in

ISRN Cell Biology 11

intracellular membrane transportrdquo Physiological Reviews vol81 no 4 pp 1689ndash1723 2001

[41] D K Banfield ldquoMechanisms of protein retention in the GolgirdquoCold Spring Harbor Perspectives in Biology vol 3 Article IDa005264 2011

[42] D J Gill J Chia J Senewiratne and F Bard ldquoRegulation ofO-glycosylation through Golgi-to-ER relocation of initiationenzymesrdquo Journal of Cell Biology vol 189 no 5 pp 843ndash8582010

[43] A Sesso F Paulo de Faria E S M Iwamura and H Correa ldquoAthree-dimensional reconstruction study of the rough ER-Golgiinterface in serial thin sections of the pancreatic acinar cell ofthe ratrdquo Journal of Cell Science vol 107 no 3 pp 517ndash528 1994

[44] Y Clermont A Rambourg and L Hermo ldquoConnectionsbetween the various elements of the cis- and mid-compart-ments of the Golgi apparatus of early rat spermatidsrdquo Anatomi-cal Record vol 240 no 4 pp 469ndash480 1994

[45] A Rambourg and Y Clermont ldquoThree-dimensional structureof the Golgi apparatus in mammalian cellsrdquo in The GolgiApparatus E G Berger and J Roth Eds pp 37ndash61 BirkhauserBasel Switzerland 1997

[46] G Vivero-Salmeron J Ballesta and J A Martınez-MenarguezldquoHeterotypic tubular connections at the endoplasmic reticu-lum-Golgi complex interfacerdquo Histochemistry and Cell Biologyvol 130 pp 709ndash717 2008

[47] C vanVliet E CThomas AMerino-Trigo R D Teasdale andP A Gleeson ldquoIntracellular sorting and transport of proteinsrdquoProgress in Biophysics and Molecular Biology vol 83 no 1 pp1ndash45 2003

[48] G Griffiths S Pfeiffer K Simons and K Matlin ldquoExit of newlysynthesized membrane proteins from the trans cisterna of theGolgi complex to the plasmamembranerdquo Journal of Cell Biologyvol 101 no 3 pp 949ndash964 1985

[49] G Griffiths S D Fuller R BackMHollinshead S Pfeiffer andK Simons ldquoThe dynamic nature of the Golgi complexrdquo Journalof Cell Biology vol 108 no 2 pp 277ndash297 1989

[50] H J Geuze and D J Morre ldquoTrans-Golgi reticulumrdquo Journal ofElectron Microscopy Technique vol 17 no 1 pp 24ndash34 1991

[51] Y Clermont A Rambourg and L Hermo ldquoTrans-Golgi net-work (TGN) of different cell types three-dimensional structuralcharacteristics and variabilityrdquo Anatomical Record vol 242 no3 pp 289ndash301 1995

[52] R S Polishchuk andA AMironov ldquoStructural aspects of Golgifunctionrdquo Cellular andMolecular Life Sciences vol 61 no 2 pp146ndash158 2004

[53] P A Gleeson J G Lock M R Luke and J L Stow ldquoDomainsof the TGN coats tethers and G proteinsrdquo Traffic vol 5 no 5pp 315ndash326 2004

[54] F Bard and V Malhotra ldquoThe formation of TGN-to-plasma-membrane transport carriersrdquo Annual Review of Cell andDevelopmental Biology vol 22 pp 439ndash455 2006

[55] R D Klausner J G Donaldson and J Lippincott-SchwartzldquoBrefeldin A insights into the control of membrane traffic andorganelle structurerdquo Journal of Cell Biology vol 116 no 5 pp1071ndash1080 1992

[56] J Llopis J M McCaffery A Miyawaki M G Farquhar andR Y Tsien ldquoMeasurement of cytosolic mitochondrial andGolgi pH in single living cells with green fluorescent proteinsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 12 pp 6803ndash6808 1998

[57] H HMollenhauer andD J Morre ldquoThe tubular network of theGolgi apparatusrdquo Histochemistry and Cell Biology vol 109 no5-6 pp 533ndash543 1998

[58] L Orci A Perrelet and J E Rothman ldquoVesicles on stringsMorphological evidence for processive transport within theGolgi stackrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 95 no 5 pp 2279ndash2283 1998

[59] Y Xiang and Y Wang ldquoNew components of the Golgi matrixrdquoCell and Tissue Research vol 344 no 3 pp 365ndash379 2011

[60] N Nakamura C Rabouille R Watson et al ldquoCharacterizationof a cis-Golgi matrix protein GM130rdquo Journal of Cell Biologyvol 131 no 6 pp 1715ndash1726 1995

[61] P Slusarewicz T Nilsson N Hui R Watson and G WarrenldquoIsolation of amatrix that bindsmedial Golgi enzymesrdquo Journalof Cell Biology vol 124 no 4 pp 405ndash413 1994

[62] G Egea and R M Rios ldquoThe role of the cytoskeleton in thestructure and function of the Golgi apparatusrdquo in The GolgiApparatus A A Mironov and M Pavelka Eds pp 270ndash300Springer NewYork NY USA 2008

[63] M Lowe ldquoStructural organization of the Golgi apparatusrdquoCurrent Opinion in Cell Biology vol 23 no 1 pp 85ndash93 2011

[64] R M Rios and M Bornens ldquoThe Golgi apparatus at the cellcentrerdquoCurrent Opinion in Cell Biology vol 15 pp 60ndash66 2003

[65] S Yadav and A D Linstedt ldquoGolgi positioningrdquo Cold SpringHarbor Perspectives in Biology vol 3 pp 1ndash17 2011

[66] J K Burkhardt ldquoThe role of microtubule-based motor proteinsin maintaining the structure and function of the Golgi com-plexrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp 113ndash126 1998

[67] K Chabin-Brion J Marceiller F Perez et al ldquoThe Golgi com-plex is a microtubule-organizing organellerdquo Molecular Biologyof the Cell vol 12 no 7 pp 2047ndash2060 2001

[68] S Rivero J Cardenas M Bornens and R M Rios ldquoMicro-tubule nucleation at the cis-side of the golgi apparatus requiresAKAP450 and GM130rdquo The EMBO Journal vol 28 no 8 pp1016ndash1028 2009

[69] A Efimov A Kharitonov N Efimova et al ldquoAsymmetricCLASP-dependent nucleation of noncentrosomal microtubulesat the trans-Golgi Networkrdquo Developmental Cell vol 12 no 6pp 917ndash930 2007

[70] P M Miller A W Folkmann A R R Maia N EfimovaA Efimov and I Kaverina ldquoGolgi-derived CLASP-dependentmicrotubules control Golgi organization and polarized traffick-ing in motile cellsrdquo Nature Cell Biology vol 11 no 9 pp 1069ndash1080 2009

[71] F Valderrama A Luna T Babia et al ldquoThe Golgi-associatedCOPI-coated buds and vesicles contain 120573120574-actinrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 97 no 4 pp 1560ndash1565 2000

[72] G Egea F Lazaro-Dieguez and M Vilella ldquoActin dynamics atthe Golgi complex inmammalian cellsrdquoCurrent Opinion in CellBiology vol 18 pp 168ndash178 2006

[73] F Lazaro-Dieguez C Colonna M Cortegano M Calvo S EMartınez and G Egea ldquoVariable actin dynamics requirementfor the exit of different cargo from the trans-Golgi networkrdquoFEBS Letters vol 581 no 20 pp 3875ndash3881 2007

[74] F Valderrama J M Duran T Babia H Barth J Renau-Piqueras and G Egea ldquoActin microfilaments facilitate theretrogade transport from the Golgi complex to the endoplasmicreticulum in mammalian cellsrdquo Traffic vol 2 no 10 pp 717ndash726 2001

12 ISRN Cell Biology

[75] A Disanza and G Scita ldquoCytoskeletal regulation coordinatingactin and microtubule dynamics in membrane traffickingrdquoCurrent Biology vol 18 no 18 pp R873ndashR875 2008

[76] K G Campellone N J Webb E A Znameroski and M DWelch ldquoWHAMM is an Arp23 complex activator that bindsmicrotubules and functions in ER to golgi transportrdquo Cell vol134 no 1 pp 148ndash161 2008

[77] Q T Shen P P Hsiue C V Sindelar M D Welch KG Campellone and H W Wang ldquoStructural insights intoWHAMM-mediated cytoskeletal coordination during mem-brane remodelingrdquoThe Journal of Cell Biology vol 199 pp 111ndash124 2012

[78] T F Roth and K R Porter ldquoYolk protein uptake in the oocyteof the mosquito Aedes aegypti Lrdquo The Journal of Cell Biologyvol 20 pp 313ndash332 1964

[79] B M F Pearse ldquoClathrin a unique protein associated withintracellular transfer of membrane by coated vesiclesrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 73 no 4 pp 1255ndash1259 1976

[80] A Oprins R Duden T E Kreis H J Geuze and J W Slotldquo120573-COP localizes mainly to the cis-Golgi side in exocrinepancreasrdquo Journal of Cell Biology vol 121 no 1 pp 49ndash60 1993

[81] B M F Pearse and M S Robinson ldquoClathrin adaptors andsortingrdquo Annual Review of Cell Biology vol 6 pp 151ndash171 1990

[82] T Braulke and J S Bonifacino ldquoSorting of lysosomal proteinsrdquoBiochimica et BiophysicaActa vol 1793 no 4 pp 605ndash614 2009

[83] T Kirchhausen ldquoClathrinrdquo Annual Review of Biochemistry vol69 pp 699ndash727 2000

[84] E Rodriguez-Boulan and A Musch ldquoProtein sorting in theGolgi complex shifting paradigmsrdquo Biochimica et BiophysicaActa vol 1744 no 3 pp 455ndash464 2005

[85] M A McNiven H Cao K R Pitts and Y Yoon ldquoThe dynaminfamily of mechanoenzymes pinching in new placesrdquo Trends inBiochemical Sciences vol 25 no 3 pp 115ndash120 2000

[86] E Eisenberg and L E Greene ldquoMultiple roles of auxilin andHsc70 in clathrin-mediated endocytosisrdquo Traffic vol 8 no 6pp 640ndash646 2007

[87] C Barlowe L Orci T Yeung et al ldquoCOPII a membrane coatformed by sec proteins that drive vesicle budding from theendoplasmic reticulumrdquo Cell vol 77 no 6 pp 895ndash907 1994

[88] L C Bickford E Mossessova and J Goldberg ldquoA structuralview of the COPII vesicle coatrdquo Current Opinion in StructuralBiology vol 14 no 2 pp 147ndash153 2004

[89] D Jensen and R Schekman ldquoCOPII-mediated vesicle forma-tion at a glancerdquo Journal of Cell Science vol 124 no 1 pp 1ndash42011

[90] T Kirchhausen ldquoMaking COPII coatsrdquo Cell vol 129 no 7 pp1251ndash1252 2007

[91] C Barlowe ldquoCOPII and selective export from the endoplasmicreticulumrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp67ndash76 1998

[92] J A Martınez-Menarguez H J Geuze J W Slot and JKlumperman ldquoVesicular tubular clusters between the ER andGolgi mediate concentration of soluble secretory proteins byexclusion fromCOPI-coated vesiclesrdquoCell vol 98 no 1 pp 81ndash90 1999

[93] K Saito M Chen F Bard et al ldquoTANGO1 facilitates cargoloading at endoplasmic reticulum exit sitesrdquo Cell vol 136 no5 pp 891ndash902 2009

[94] L Jin K B Pahuja K E Wickliffe et al ldquoUbiquitin-dependentregulation of COPII coat size and functionrdquo Nature vol 482pp 495ndash500 2012

[95] H P Hauri and A Schweizer ldquoThe endoplasmic reticulum-Golgi intermediate compartmentrdquo Current Opinion in CellBiology vol 4 no 4 pp 600ndash608 1992

[96] S I Bannykh T Rowe and W E Balch ldquoThe organizationof endoplasmic reticulum export complexesrdquo Journal of CellBiology vol 135 no 1 pp 19ndash35 1996

[97] J Saraste and E Kuismanen ldquoPre- and post-Golgi vacuolesoperate in the transport of Semliki Forest virus membraneglycoproteins to the cell surfacerdquo Cell vol 38 no 2 pp 535ndash549 1984

[98] A Schweizer J A M Fransen K Matter T E Kreis L GinselandH PHauri ldquoIdentification of an intermediate compartmentinvolved in protein transport from endoplasmic reticulum toGolgi apparatusrdquo European Journal of Cell Biology vol 53 no 2pp 185ndash196 1990

[99] H Ben-Takaya K Miura R Pepperkok and H P Hauri ldquoLiveimaging of bidirectional traffic from the ERGICrdquo Journal of CellScience vol 118 no 2 pp 357ndash367 2005

[100] Y C Zhang Y Zhou C Z Yang and D S Xiong ldquoA reviewof ERGIC-53 its structure functions regulation and relationswith diseasesrdquo Histology and Histopathology vol 24 no 9 pp1193ndash1204 2009

[101] J F Presley N B Cole T A Schroer K Hirschberg K JM Zaal and J Lippincott-Schwartz ldquoER-to-Golgi transportvisualized in living cellsrdquo Nature vol 389 no 6646 pp 81ndash851997

[102] J A Martınez-Menarguez H J Geuze and J Ballesta ldquoIdenti-fication of two types of beta-COP vesicles in the Golgi complexof rat spermatidsrdquo European Journal of Cell Biology vol 71 pp137ndash143 1996

[103] J Lippincott-Schwartz J G Donaldson A Schweizer et alldquoMicrotubule-dependent retrograde transport of proteins intothe ER in the presence of brefeldin A suggests an ER recyclingpathwayrdquo Cell vol 60 no 5 pp 821ndash836 1990

[104] A Girod B Storrie J C Simpson et al ldquoEvidence for a COP-I-independent transport route from the Golgi complex to theendoplasmic reticulumrdquo Nature Cell Biology vol 1 no 7 pp423ndash430 1999

[105] V Popoff F Adolf B Brugger and F Wieland ldquoCOPI buddingwithin the Golgi stackrdquo Cold Spring Harbor Perspectives inBiology vol 3 Article ID a005231 2011

[106] J Moelleken J Malsam M J Betts et al ldquoDifferential localiza-tion of coatomer complex isoforms within the Golgi apparatusrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 104 no 11 pp 4425ndash4430 2007

[107] L Orci B S Glick and J E Rothman ldquoA new type of coatedvesicular carrier that appears not to contain clathrin its possiblerole in protein transport within theGolgi stackrdquoCell vol 46 no2 pp 171ndash184 1986

[108] V Malhotra T Serafini L Orci J C Shepherd and J ERothman ldquoPurification of a novel class of coated vesiclesmediating biosynthetic protein transport through the Golgistackrdquo Cell vol 58 no 2 pp 329ndash336 1989

[109] M G Waters T Serafini and J E Rothman ldquolsquoCoatomerrsquo acytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesiclesrdquo Nature vol 349 no 6306 pp248ndash251 1991

[110] T Serafini L Orci M Amherdt M Brunner R A Kahn andJ E Rothman ldquoADP-ribosylation factor is a subunit of the coatof Golgi-derived COP-coated vesicles a novel role for a GTP-binding proteinrdquo Cell vol 67 no 2 pp 239ndash253 1991

ISRN Cell Biology 13

[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

[112] K Kawamoto Y Yoshida H Tamaki et al ldquoGBF1 a guaninenucleotide exchange factor for ADP-ribosylation factors islocalized to the cis-Golgi and involved inmembrane associationof the COPI coatrdquo Traffic vol 3 no 7 pp 483ndash495 2002

[113] R Garcıa-Mata T Szul C Alvarez and E Sztul ldquoADP-ribosylation factorCOPI-dependent events at the endoplas-mic reticulum-Golgi interface are regulated by the guaninenucleotide exchange factor GBF1rdquoMolecular Biology of the Cellvol 14 no 6 pp 2250ndash2261 2003

[114] H Inoue and P A Randazzo ldquoArf GAPs and their interactingproteinsrdquo Traffic vol 8 no 11 pp 1465ndash1475 2007

[115] G Tanigawa L Orci M Amherdt M Ravazzola J B Helmsand J E Rothman ldquoHydrolysis of bound GTP by ARF proteintriggers uncoating of Golgi- derived COP-coated vesiclesrdquoJournal of Cell Biology vol 123 no 6 pp 1365ndash1371 1993

[116] Y Shiba and P A Randazzo ldquoArfGAP1 function in COPImediated membrane traffic currently debated models andcomparison to other coat-binding ArfGAPsrdquo Histology andHistopathology vol 27 pp 1143ndash1153 2012

[117] J Bigay P Gounon S Roblneau and B Antonny ldquoLipidpacking sensed by ArfGAP1 couples COPI coat disassembly tomembrane bilayer curvaturerdquo Nature vol 426 no 6966 pp563ndash566 2003

[118] W Nickel J Malsam K Gorgas et al ldquoUptake by COPI-coatedvesicles of both anterograde and retrograde cargo is inhibitedby GTP120574S in vitrordquo Journal of Cell Science vol 111 no 20 pp3081ndash3090 1998

[119] R Beck M Rawet F T Wieland and D Cassel ldquoThe COPIsystemmolecularmechanisms and functionrdquo FEBS Letters vol583 pp 2701ndash2709 2009

[120] F Letourneur E C Gaynor S Hennecke et al ldquoCoatomeris essential for retrieval of dilysine-tagged proteins to theendoplasmic reticulumrdquo Cell vol 79 no 7 pp 1199ndash1207 1994

[121] R Schindler C Itin M Zerial F Lottspeich and H P HaurildquoERGIC-53 a membrane protein of the ER-Golgi intermediatecompartment carries an ER retention motifrdquo European Journalof Cell Biology vol 61 no 1 pp 1ndash9 1993

[122] L P Jackson M Lewis H M Kent et al ldquoMolecular basis forrecognition of dilysine trafficking motifs by COPIrdquo Develop-mental Cell vol 23 pp 1ndash8 2012

[123] W Nickel K Sohn C Bunning and F T Wieland ldquop23 Amajor COPI-vesicle membrane protein constitutively cyclesthrough the early secretory pathwayrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 94 no21 pp 11393ndash11398 1997

[124] J C Semenza K G Hardwick N Dean and H R BPelham ldquoERD2 a yeast gene required for the receptor-mediatedretrieval of luminal ER proteins from the secretory pathwayrdquoCell vol 61 no 7 pp 1349ndash1357 1990

[125] I Majoul M Straub S W Hell R Duden and H D SolingldquoKDEL-cargo regulates interactions between proteins involvedin COPI vesicle traffic measurements in living cells usingFRETrdquo Developmental Cell vol 1 no 1 pp 139ndash153 2001

[126] B S Glick ldquoOrganization of the Golgi apparatusrdquo CurrentOpinion in Cell Biology vol 12 no 4 pp 450ndash456 2000

[127] R Blum D J Stephens and I Schulz ldquoLumenal targeted GFPused as a marker of soluble cargo visualises rapid ERGIC toGolgi traffic by a tubulo-vesicular networkrdquo Journal of CellScience vol 113 no 18 pp 3151ndash3159 2000

[128] J C Simpson T Nilsson and R Pepperkok ldquoBiogenesis oftubular ER-to-golgi transport intermediatesrdquoMolecular Biologyof the Cell vol 17 no 2 pp 723ndash737 2006

[129] K Hirschberg C M Miller J Ellenberg et al ldquoKinetic analysisof secretory protein traffic and characterization of Golgi toplasma membrane transport intermediates in living cellsrdquoJournal of Cell Biology vol 143 no 6 pp 1485ndash1503 1998

[130] D Toomre P Keller JWhite J C Olivo and K Simons ldquoDual-color visualization of trans-Golgi network to plasmamembranetraffic alongmicrotubules in living cellsrdquo Journal of Cell Sciencevol 112 no 1 pp 21ndash33 1999

[131] L Hermo A Rambourg and Y Clermont ldquoThree-dimensionalarchitecture of the cortical region of the Golgi apparatus in ratspermatidsrdquo American Journal of Anatomy vol 157 no 4 pp357ndash373 1980

[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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BioinformaticsAdvances in

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Signal TransductionJournal of

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ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Enzyme Research

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International Journal of

Microbiology

ISRN Cell Biology 9

acquiring and then losing specific Golgi-resident proteinsThe presence of Golgi resident enzymes in COPI vesicles hasbeen demonstrated [188] although their relative concentra-tion is controversial Life cell imaging studies in yeast stronglysupport this model In Saccharomyces cerevisiae the Golgiis not stacked so that individual cisterna can be analyzedseparately Using cis and trans Golgi markers it was directlydemonstrated that cisternae mature (ie the apparentlyconversion of one type of cisterna into another) [196 197]The cisternal maturation model seems to be more efficientgiven that it would seem easier to transport anterograde cargousing a large carrier (the cisterna) than to use many smallvesicles between adjacent cisternae and repeating this processseveral times until reaching the TGN It is also intuitive thatperi-Golgi vesicles should be restricted to more selective andsmaller trafficking the retrograde pathway

63 Alternative Models Given that none of these modelscompletely explains all the experimental data new modelshave been postulated although some of them are variationsof the two main models

Dual transport model one possibility is that these twomodels are not mutually exclusive but rather complementaryand working simultaneously [198] Cisternae may moveslowly whereas vesicles transport anterograde and retrogradecargo more rapidly Large molecules may use the cisternalmaturation mechanism while small molecules can be trans-ported using vesicular transport [186 198]

Rapid partitioning model This model is based on therapid partitioning of transmembrane cargo and residentenzymes between two lipid phases According to this modelthe GC works as a single compartment but contains pro-cessing and export domains [199] When the cargo reachesthe Golgi it associates with these domains and then leavesthe compartment from every level Again this model hasdifficulty in explaining the polarity of the cisternae and doesnot help visualize the Golgi stack as a single compartment

Kiss-and-runmodelThis model is based onmechanismsoperating in other systems such as endosomes and lysosomesThismodel proposes that two cisternaemay fuse to each otherthrough narrow tubules connecting their lumens transientlyand allowing the transit of cargo before separating [200] Inthis model anterograde transport and retrograde transportoccur simultaneously and a specific retrograde pathway is notnecessary This model may explain several aspects of Golgitransport including the transport of large molecules How-ever some assumptions of the model need to be confirmed(ig machinery and mechanisms for the fusion and fission ofconnections) It is also not clear how all the experimental dataabout the role of COPI coats in retrograde transport fit thismodel

Intra-Golgi transportmediated by tubulesThe absence ofcargo in COPI vesicles suggests that other transport interme-diates such as tubules may operate at the GC As mentionedabove tubules are a common structure surrounding the stackTubules may be involved in the anterograde movement ofcargo through this organelleThe ER and all cisternae may bedirectly connected by tubules and cargo might move along

the secretory pathway like food through the gut [201] Infact conditions that stimulated protein secretion increasethe number of tubular connections between cisternae [136137] Conversely tubules may establish transient connectionsbetween compartments helping COPI vesicles to transportGolgi enzymes retrogradely as indicated by the cisternalmaturation model [46] (Figure 3) Cisternal maturation inyeast occurs although slowly without COPI vesicles suggest-ing that tubules may replace them [197] Low temperature-induced Golgi tubules are enriched in Golgi enzymes andSNARE and Rab proteins involved in intra-Golgi transportwhereas they exclude other proteins associated with ER-Golgi transport [139] Whether the tubules found in thismodel are representative of the carriers involved in intra-Golgi transport remains to be established

7 Concluding Remarks

A century after the discovery of the ldquoapparato reticolareinternordquo [202] it is clear that no model for intra-Golgi trans-port explains all the experimental data But it is also true thatthe ldquohigh polarityrdquo that exits the field has stimulated intenseresearch Recently developed high-resolution methodologiesmay give important clues in this respect Of special interestis the analysis of the structure and composition of tubularand vesicular carriers High-resolution immunocytochemi-cal techniques in combination with electron tomography aswell as proteomic analysis of highly purified samples maysolve the problem or at least definitively reject some modelsIn the end it is possible that each cell type depending of itsspecial characteristics uses a givenmechanism of intra-Golgitransport It also remains possible that a single cell usesdifferent mechanisms of intra-Golgi transport depending onthe amount and type of cargo or its physiological statusMeanwhile cisternal maturation in combination with tubulartransient connections is a very attractive and intuitive modelthat seems to fit most experimental data

Acknowledgments

The work in this paper was supported by Grants fromthe Ministerio de Ciencia e Innovacion (Spain) ConsoliderCOAT (CSD2009-00016) and Fundacion Seneca de la Comu-nidadAutonoma de la Region deMurcia (04542GERM06)

References

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[2] W Nickel and C Rabouille ldquoMechanisms of regulated uncon-ventional protein secretionrdquo Nature Reviews Molecular CellBiology vol 10 no 2 pp 148ndash155 2009

[3] M G Farquhar and G E Palade ldquoThe Golgi apparatus (com-plex) (1954ndash1981) from artifact to center stagerdquo Journal of CellBiology vol 91 no 3 pp 77sndash103s 1981

[4] M G Farquhar and G E Palade ldquoThe Golgi apparatus 100years of progress and controversyrdquo Trends in Cell Biology vol8 no 1 pp 2ndash10 1998

10 ISRN Cell Biology

[5] C Wilson R Venditti L R Rega A Colanzi G DrsquoAngeloandM A De ldquoThe Golgi apparatus an organelle with multiplecomplex functionsrdquo Biochemical Journal vol 433 no 1 pp 1ndash92011

[6] J Lippincott-Schwartz E Snapp and A Kemvorthy ldquoStudyingprotein dynamics in living cellsrdquoNature Reviews Molecular CellBiology vol 2 no 6 pp 444ndash456 2001

[7] G Perinetti T Muller A Spaar R Polishchuk A Luini andA Egner ldquoCorrelation of 4Pi and electron microscopy to studytransport through single golgi stacks in living cells with superresolutionrdquo Traffic vol 10 no 4 pp 379ndash391 2009

[8] J Lippincott-Schwartz ldquoEmerging in vivo analyses of cellfunction using fluorescence imagingrdquo Annual Review of Bio-chemistry vol 80 pp 327ndash332 2011

[9] A Gilchrist C E Au J Hiding et al ldquoQuantitative proteomicsanalysis of the secretory pathwayrdquo Cell vol 127 no 6 pp 1265ndash1281 2006

[10] J Gannon J J Bergeron and T Nilsson ldquoGolgi and relatedvesicle proteomics simplify to identifyrdquo Cold Spring HarborPerspectives in Biology vol 3 no 12 2011

[11] F Bard L Casano A Mallabiabarrena et al ldquoFunctionalgenomics reveals genes involved in protein secretion and Golgiorganizationrdquo Nature vol 439 pp 604ndash607 2006

[12] J W Slot and H J Geuze ldquoImmunoelectron microscopicexploration of theGolgi complexrdquo Journal ofHistochemistry andCytochemistry vol 31 no 8 pp 1049ndash1056 1983

[13] D ZeuschnerW J C Geerts E vanDonselaar et al ldquoImmuno-electron tomography of ER exit sites reveals the existence of freeCOPII-coated transport carriersrdquoNature Cell Biology vol 8 no4 pp 377ndash383 2006

[14] R S Polishchuk E V Polishchuk P Marra et al ldquoCorrelativelight-electron microscopy reveals the tubular-saccular ultra-structure of carriers operating between Golgi apparatus andplasma membranerdquo Journal of Cell Biology vol 148 no 1 pp45ndash58 2000

[15] B S Donohoe S Mogelsvang and L A Staehelin ldquoElectrontomography of ER Golgi and related membrane systemsrdquoMethods vol 39 no 2 pp 154ndash162 2006

[16] N K Gonatas A Stieber and J O Gonatas ldquoFragmentationof the Golgi apparatus in neurodegenerative diseases and celldeathrdquo Journal of the Neurological Sciences vol 246 no 1-2 pp21ndash30 2006

[17] M C Derby and P A Gleeson ldquoNew insights into membranetrafficking and protein sortingrdquo International Review of Cytol-ogy vol 261 pp 47ndash116 2007

[18] A A Mironov and M Pavelka The Golgi Apparatus State ofthe Art 110 Years after Camillo Golgirsquos Discovery Springer WienNewYork NY USA 2008

[19] E Papanikou and B S Glick ldquoThe yeast Golgi apparatusinsights and mysteriesrdquo FEBS Letters vol 583 no 23 pp 3746ndash3751 2009

[20] J H Wei and J Seemann ldquoMitotic division of the mammalianGolgi apparatusrdquo Seminars in Cell and Developmental Biologyvol 20 no 7 pp 810ndash816 2009

[21] M Anitei and B Hoflack ldquoExit from the trans-Golgi networkfrom molecules to mechanismsrdquo Current Opinion in Cell Biol-ogy vol 23 no 4 pp 443ndash451 2011

[22] J Klumperman ldquoArchitecture of the mammalian Golgirdquo ColdSpring Harbor Perspectives in Biology vol 3 no 7 Article IDa005181 2011

[23] YWang and J Seemann ldquoGolgi biogenesisrdquoCold Spring HarborPerspectives in Biology vol 3 no 10 Article ID a005330 2011

[24] K W Moremen M Tiemeyer and A V Nairn ldquoVertebrateprotein glycosylation diversity synthesis and functionrdquoNatureReviews Molecular Cell Biology vol 13 pp 448ndash462 2012

[25] A J Dalton and M D Felix ldquoA comparative study of the Golgicomplexrdquo The Journal of Biophysical and Biochemical Cytologyvol 2 no 4 pp 79ndash84 1956

[26] A Rambourg Y Clermont and A Marraud ldquoThree dimen-sional structure of the osmium impregnated Golgi apparatus asseen in the high voltage electronmicroscoperdquoAmerican Journalof Anatomy vol 140 no 1 pp 27ndash46 1974

[27] A Rambourg Y Clermont and L Hermo ldquoThree-dimensionalarchitecture of the Golgi apparatus in Sertoli cells of the ratrdquoAmerican Journal of Anatomy vol 154 no 4 pp 455ndash476 1979

[28] M S Ladinsky D NMastronarde J RMcIntosh K E Howelland L A Staehelin ldquoGolgi structure in three dimensionsfunctional insights from the normal rat kidney cellrdquo Journal ofCell Biology vol 144 no 6 pp 1135ndash1149 1999

[29] R S Taylor S M Jones R H Dahl M H Nordeen andK E Howell ldquoCharacterization of the Golgi complex clearedof proteins in transit and examination of calcium uptakeactivitiesrdquo Molecular Biology of the Cell vol 8 no 10 pp 1911ndash1931 1997

[30] MMWuM Grabe S Adams R Y Tsien H P HMoore andT E Machen ldquoMechanisms of pH regulation in the regulatedsecretory pathwayrdquo Journal of Biological Chemistry vol 276 no35 pp 33027ndash33035 2001

[31] J HWei and J Seemann ldquoUnraveling theGolgi ribbonrdquoTrafficvol 11 no 11 pp 1391ndash1400 2010

[32] A A Mironov and G V Beznoussenko ldquoMolecular mecha-nisms responsible for formation of Golgi ribbonrdquoHistology andHistopathology vol 26 no 1 pp 117ndash133 2011

[33] B Storrie JWhite S Rottger E H K Stelzer T Suganuma andT Nilsson ldquoRecycling of Golgi-resident glycosyltransferasesthrough the ER reveals a novel pathway and provides anexplanation for nocodazole-induced Golgi scatteringrdquo Journalof Cell Biology vol 143 no 6 pp 1505ndash1521 1998

[34] J Fan Z Hu L Zeng et al ldquoGolgi apparatus and neurode-generative diseasesrdquo International Journal of DevelopmentalNeuroscience vol 26 no 6 pp 523ndash534 2008

[35] Y Fujita EOhamaMTakatama S Al-Sarraj andKOkamotoldquoFragmentation of Golgi apparatus of nigral neurons with120572-synuclein-positive inclusions in patients with Parkinsonrsquosdiseaserdquo Acta Neuropathologica vol 112 no 3 pp 261ndash2652006

[36] G Thorne-Tjomsland M Dumontier and J C Jamiesonldquo3D topography of noncompact zone Golgi tubules in ratspermatids a computer-assisted serial section reconstructionstudyrdquoThe Anatomical Record vol 250 pp 381ndash396 1998

[37] A S Opat C Van Vliet and P A Gleeson ldquoTrafficking andlocalisation of residentGolgi glycosylation enzymesrdquoBiochimievol 83 no 8 pp 763ndash773 2001

[38] M G Farquhar and H P Hauri ldquoProtein sorting and vesiculartraffic in the Golgi apparatusrdquo inTheGolgi Apparatus E Bergerand J Roth Eds pp 63ndash128 Birkhauser Basel Switzerland1997

[39] G van Meer ldquoLipids of the Golgi membranerdquo Trends in CellBiology vol 8 no 1 pp 29ndash33 1998

[40] J C M Holthuis T Pomorski R J Raggers H Sprong andG Van Meer ldquoThe organizing potential of sphingolipids in

ISRN Cell Biology 11

intracellular membrane transportrdquo Physiological Reviews vol81 no 4 pp 1689ndash1723 2001

[41] D K Banfield ldquoMechanisms of protein retention in the GolgirdquoCold Spring Harbor Perspectives in Biology vol 3 Article IDa005264 2011

[42] D J Gill J Chia J Senewiratne and F Bard ldquoRegulation ofO-glycosylation through Golgi-to-ER relocation of initiationenzymesrdquo Journal of Cell Biology vol 189 no 5 pp 843ndash8582010

[43] A Sesso F Paulo de Faria E S M Iwamura and H Correa ldquoAthree-dimensional reconstruction study of the rough ER-Golgiinterface in serial thin sections of the pancreatic acinar cell ofthe ratrdquo Journal of Cell Science vol 107 no 3 pp 517ndash528 1994

[44] Y Clermont A Rambourg and L Hermo ldquoConnectionsbetween the various elements of the cis- and mid-compart-ments of the Golgi apparatus of early rat spermatidsrdquo Anatomi-cal Record vol 240 no 4 pp 469ndash480 1994

[45] A Rambourg and Y Clermont ldquoThree-dimensional structureof the Golgi apparatus in mammalian cellsrdquo in The GolgiApparatus E G Berger and J Roth Eds pp 37ndash61 BirkhauserBasel Switzerland 1997

[46] G Vivero-Salmeron J Ballesta and J A Martınez-MenarguezldquoHeterotypic tubular connections at the endoplasmic reticu-lum-Golgi complex interfacerdquo Histochemistry and Cell Biologyvol 130 pp 709ndash717 2008

[47] C vanVliet E CThomas AMerino-Trigo R D Teasdale andP A Gleeson ldquoIntracellular sorting and transport of proteinsrdquoProgress in Biophysics and Molecular Biology vol 83 no 1 pp1ndash45 2003

[48] G Griffiths S Pfeiffer K Simons and K Matlin ldquoExit of newlysynthesized membrane proteins from the trans cisterna of theGolgi complex to the plasmamembranerdquo Journal of Cell Biologyvol 101 no 3 pp 949ndash964 1985

[49] G Griffiths S D Fuller R BackMHollinshead S Pfeiffer andK Simons ldquoThe dynamic nature of the Golgi complexrdquo Journalof Cell Biology vol 108 no 2 pp 277ndash297 1989

[50] H J Geuze and D J Morre ldquoTrans-Golgi reticulumrdquo Journal ofElectron Microscopy Technique vol 17 no 1 pp 24ndash34 1991

[51] Y Clermont A Rambourg and L Hermo ldquoTrans-Golgi net-work (TGN) of different cell types three-dimensional structuralcharacteristics and variabilityrdquo Anatomical Record vol 242 no3 pp 289ndash301 1995

[52] R S Polishchuk andA AMironov ldquoStructural aspects of Golgifunctionrdquo Cellular andMolecular Life Sciences vol 61 no 2 pp146ndash158 2004

[53] P A Gleeson J G Lock M R Luke and J L Stow ldquoDomainsof the TGN coats tethers and G proteinsrdquo Traffic vol 5 no 5pp 315ndash326 2004

[54] F Bard and V Malhotra ldquoThe formation of TGN-to-plasma-membrane transport carriersrdquo Annual Review of Cell andDevelopmental Biology vol 22 pp 439ndash455 2006

[55] R D Klausner J G Donaldson and J Lippincott-SchwartzldquoBrefeldin A insights into the control of membrane traffic andorganelle structurerdquo Journal of Cell Biology vol 116 no 5 pp1071ndash1080 1992

[56] J Llopis J M McCaffery A Miyawaki M G Farquhar andR Y Tsien ldquoMeasurement of cytosolic mitochondrial andGolgi pH in single living cells with green fluorescent proteinsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 12 pp 6803ndash6808 1998

[57] H HMollenhauer andD J Morre ldquoThe tubular network of theGolgi apparatusrdquo Histochemistry and Cell Biology vol 109 no5-6 pp 533ndash543 1998

[58] L Orci A Perrelet and J E Rothman ldquoVesicles on stringsMorphological evidence for processive transport within theGolgi stackrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 95 no 5 pp 2279ndash2283 1998

[59] Y Xiang and Y Wang ldquoNew components of the Golgi matrixrdquoCell and Tissue Research vol 344 no 3 pp 365ndash379 2011

[60] N Nakamura C Rabouille R Watson et al ldquoCharacterizationof a cis-Golgi matrix protein GM130rdquo Journal of Cell Biologyvol 131 no 6 pp 1715ndash1726 1995

[61] P Slusarewicz T Nilsson N Hui R Watson and G WarrenldquoIsolation of amatrix that bindsmedial Golgi enzymesrdquo Journalof Cell Biology vol 124 no 4 pp 405ndash413 1994

[62] G Egea and R M Rios ldquoThe role of the cytoskeleton in thestructure and function of the Golgi apparatusrdquo in The GolgiApparatus A A Mironov and M Pavelka Eds pp 270ndash300Springer NewYork NY USA 2008

[63] M Lowe ldquoStructural organization of the Golgi apparatusrdquoCurrent Opinion in Cell Biology vol 23 no 1 pp 85ndash93 2011

[64] R M Rios and M Bornens ldquoThe Golgi apparatus at the cellcentrerdquoCurrent Opinion in Cell Biology vol 15 pp 60ndash66 2003

[65] S Yadav and A D Linstedt ldquoGolgi positioningrdquo Cold SpringHarbor Perspectives in Biology vol 3 pp 1ndash17 2011

[66] J K Burkhardt ldquoThe role of microtubule-based motor proteinsin maintaining the structure and function of the Golgi com-plexrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp 113ndash126 1998

[67] K Chabin-Brion J Marceiller F Perez et al ldquoThe Golgi com-plex is a microtubule-organizing organellerdquo Molecular Biologyof the Cell vol 12 no 7 pp 2047ndash2060 2001

[68] S Rivero J Cardenas M Bornens and R M Rios ldquoMicro-tubule nucleation at the cis-side of the golgi apparatus requiresAKAP450 and GM130rdquo The EMBO Journal vol 28 no 8 pp1016ndash1028 2009

[69] A Efimov A Kharitonov N Efimova et al ldquoAsymmetricCLASP-dependent nucleation of noncentrosomal microtubulesat the trans-Golgi Networkrdquo Developmental Cell vol 12 no 6pp 917ndash930 2007

[70] P M Miller A W Folkmann A R R Maia N EfimovaA Efimov and I Kaverina ldquoGolgi-derived CLASP-dependentmicrotubules control Golgi organization and polarized traffick-ing in motile cellsrdquo Nature Cell Biology vol 11 no 9 pp 1069ndash1080 2009

[71] F Valderrama A Luna T Babia et al ldquoThe Golgi-associatedCOPI-coated buds and vesicles contain 120573120574-actinrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 97 no 4 pp 1560ndash1565 2000

[72] G Egea F Lazaro-Dieguez and M Vilella ldquoActin dynamics atthe Golgi complex inmammalian cellsrdquoCurrent Opinion in CellBiology vol 18 pp 168ndash178 2006

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[74] F Valderrama J M Duran T Babia H Barth J Renau-Piqueras and G Egea ldquoActin microfilaments facilitate theretrogade transport from the Golgi complex to the endoplasmicreticulum in mammalian cellsrdquo Traffic vol 2 no 10 pp 717ndash726 2001

12 ISRN Cell Biology

[75] A Disanza and G Scita ldquoCytoskeletal regulation coordinatingactin and microtubule dynamics in membrane traffickingrdquoCurrent Biology vol 18 no 18 pp R873ndashR875 2008

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[77] Q T Shen P P Hsiue C V Sindelar M D Welch KG Campellone and H W Wang ldquoStructural insights intoWHAMM-mediated cytoskeletal coordination during mem-brane remodelingrdquoThe Journal of Cell Biology vol 199 pp 111ndash124 2012

[78] T F Roth and K R Porter ldquoYolk protein uptake in the oocyteof the mosquito Aedes aegypti Lrdquo The Journal of Cell Biologyvol 20 pp 313ndash332 1964

[79] B M F Pearse ldquoClathrin a unique protein associated withintracellular transfer of membrane by coated vesiclesrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 73 no 4 pp 1255ndash1259 1976

[80] A Oprins R Duden T E Kreis H J Geuze and J W Slotldquo120573-COP localizes mainly to the cis-Golgi side in exocrinepancreasrdquo Journal of Cell Biology vol 121 no 1 pp 49ndash60 1993

[81] B M F Pearse and M S Robinson ldquoClathrin adaptors andsortingrdquo Annual Review of Cell Biology vol 6 pp 151ndash171 1990

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[83] T Kirchhausen ldquoClathrinrdquo Annual Review of Biochemistry vol69 pp 699ndash727 2000

[84] E Rodriguez-Boulan and A Musch ldquoProtein sorting in theGolgi complex shifting paradigmsrdquo Biochimica et BiophysicaActa vol 1744 no 3 pp 455ndash464 2005

[85] M A McNiven H Cao K R Pitts and Y Yoon ldquoThe dynaminfamily of mechanoenzymes pinching in new placesrdquo Trends inBiochemical Sciences vol 25 no 3 pp 115ndash120 2000

[86] E Eisenberg and L E Greene ldquoMultiple roles of auxilin andHsc70 in clathrin-mediated endocytosisrdquo Traffic vol 8 no 6pp 640ndash646 2007

[87] C Barlowe L Orci T Yeung et al ldquoCOPII a membrane coatformed by sec proteins that drive vesicle budding from theendoplasmic reticulumrdquo Cell vol 77 no 6 pp 895ndash907 1994

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[89] D Jensen and R Schekman ldquoCOPII-mediated vesicle forma-tion at a glancerdquo Journal of Cell Science vol 124 no 1 pp 1ndash42011

[90] T Kirchhausen ldquoMaking COPII coatsrdquo Cell vol 129 no 7 pp1251ndash1252 2007

[91] C Barlowe ldquoCOPII and selective export from the endoplasmicreticulumrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp67ndash76 1998

[92] J A Martınez-Menarguez H J Geuze J W Slot and JKlumperman ldquoVesicular tubular clusters between the ER andGolgi mediate concentration of soluble secretory proteins byexclusion fromCOPI-coated vesiclesrdquoCell vol 98 no 1 pp 81ndash90 1999

[93] K Saito M Chen F Bard et al ldquoTANGO1 facilitates cargoloading at endoplasmic reticulum exit sitesrdquo Cell vol 136 no5 pp 891ndash902 2009

[94] L Jin K B Pahuja K E Wickliffe et al ldquoUbiquitin-dependentregulation of COPII coat size and functionrdquo Nature vol 482pp 495ndash500 2012

[95] H P Hauri and A Schweizer ldquoThe endoplasmic reticulum-Golgi intermediate compartmentrdquo Current Opinion in CellBiology vol 4 no 4 pp 600ndash608 1992

[96] S I Bannykh T Rowe and W E Balch ldquoThe organizationof endoplasmic reticulum export complexesrdquo Journal of CellBiology vol 135 no 1 pp 19ndash35 1996

[97] J Saraste and E Kuismanen ldquoPre- and post-Golgi vacuolesoperate in the transport of Semliki Forest virus membraneglycoproteins to the cell surfacerdquo Cell vol 38 no 2 pp 535ndash549 1984

[98] A Schweizer J A M Fransen K Matter T E Kreis L GinselandH PHauri ldquoIdentification of an intermediate compartmentinvolved in protein transport from endoplasmic reticulum toGolgi apparatusrdquo European Journal of Cell Biology vol 53 no 2pp 185ndash196 1990

[99] H Ben-Takaya K Miura R Pepperkok and H P Hauri ldquoLiveimaging of bidirectional traffic from the ERGICrdquo Journal of CellScience vol 118 no 2 pp 357ndash367 2005

[100] Y C Zhang Y Zhou C Z Yang and D S Xiong ldquoA reviewof ERGIC-53 its structure functions regulation and relationswith diseasesrdquo Histology and Histopathology vol 24 no 9 pp1193ndash1204 2009

[101] J F Presley N B Cole T A Schroer K Hirschberg K JM Zaal and J Lippincott-Schwartz ldquoER-to-Golgi transportvisualized in living cellsrdquo Nature vol 389 no 6646 pp 81ndash851997

[102] J A Martınez-Menarguez H J Geuze and J Ballesta ldquoIdenti-fication of two types of beta-COP vesicles in the Golgi complexof rat spermatidsrdquo European Journal of Cell Biology vol 71 pp137ndash143 1996

[103] J Lippincott-Schwartz J G Donaldson A Schweizer et alldquoMicrotubule-dependent retrograde transport of proteins intothe ER in the presence of brefeldin A suggests an ER recyclingpathwayrdquo Cell vol 60 no 5 pp 821ndash836 1990

[104] A Girod B Storrie J C Simpson et al ldquoEvidence for a COP-I-independent transport route from the Golgi complex to theendoplasmic reticulumrdquo Nature Cell Biology vol 1 no 7 pp423ndash430 1999

[105] V Popoff F Adolf B Brugger and F Wieland ldquoCOPI buddingwithin the Golgi stackrdquo Cold Spring Harbor Perspectives inBiology vol 3 Article ID a005231 2011

[106] J Moelleken J Malsam M J Betts et al ldquoDifferential localiza-tion of coatomer complex isoforms within the Golgi apparatusrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 104 no 11 pp 4425ndash4430 2007

[107] L Orci B S Glick and J E Rothman ldquoA new type of coatedvesicular carrier that appears not to contain clathrin its possiblerole in protein transport within theGolgi stackrdquoCell vol 46 no2 pp 171ndash184 1986

[108] V Malhotra T Serafini L Orci J C Shepherd and J ERothman ldquoPurification of a novel class of coated vesiclesmediating biosynthetic protein transport through the Golgistackrdquo Cell vol 58 no 2 pp 329ndash336 1989

[109] M G Waters T Serafini and J E Rothman ldquolsquoCoatomerrsquo acytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesiclesrdquo Nature vol 349 no 6306 pp248ndash251 1991

[110] T Serafini L Orci M Amherdt M Brunner R A Kahn andJ E Rothman ldquoADP-ribosylation factor is a subunit of the coatof Golgi-derived COP-coated vesicles a novel role for a GTP-binding proteinrdquo Cell vol 67 no 2 pp 239ndash253 1991

ISRN Cell Biology 13

[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

[112] K Kawamoto Y Yoshida H Tamaki et al ldquoGBF1 a guaninenucleotide exchange factor for ADP-ribosylation factors islocalized to the cis-Golgi and involved inmembrane associationof the COPI coatrdquo Traffic vol 3 no 7 pp 483ndash495 2002

[113] R Garcıa-Mata T Szul C Alvarez and E Sztul ldquoADP-ribosylation factorCOPI-dependent events at the endoplas-mic reticulum-Golgi interface are regulated by the guaninenucleotide exchange factor GBF1rdquoMolecular Biology of the Cellvol 14 no 6 pp 2250ndash2261 2003

[114] H Inoue and P A Randazzo ldquoArf GAPs and their interactingproteinsrdquo Traffic vol 8 no 11 pp 1465ndash1475 2007

[115] G Tanigawa L Orci M Amherdt M Ravazzola J B Helmsand J E Rothman ldquoHydrolysis of bound GTP by ARF proteintriggers uncoating of Golgi- derived COP-coated vesiclesrdquoJournal of Cell Biology vol 123 no 6 pp 1365ndash1371 1993

[116] Y Shiba and P A Randazzo ldquoArfGAP1 function in COPImediated membrane traffic currently debated models andcomparison to other coat-binding ArfGAPsrdquo Histology andHistopathology vol 27 pp 1143ndash1153 2012

[117] J Bigay P Gounon S Roblneau and B Antonny ldquoLipidpacking sensed by ArfGAP1 couples COPI coat disassembly tomembrane bilayer curvaturerdquo Nature vol 426 no 6966 pp563ndash566 2003

[118] W Nickel J Malsam K Gorgas et al ldquoUptake by COPI-coatedvesicles of both anterograde and retrograde cargo is inhibitedby GTP120574S in vitrordquo Journal of Cell Science vol 111 no 20 pp3081ndash3090 1998

[119] R Beck M Rawet F T Wieland and D Cassel ldquoThe COPIsystemmolecularmechanisms and functionrdquo FEBS Letters vol583 pp 2701ndash2709 2009

[120] F Letourneur E C Gaynor S Hennecke et al ldquoCoatomeris essential for retrieval of dilysine-tagged proteins to theendoplasmic reticulumrdquo Cell vol 79 no 7 pp 1199ndash1207 1994

[121] R Schindler C Itin M Zerial F Lottspeich and H P HaurildquoERGIC-53 a membrane protein of the ER-Golgi intermediatecompartment carries an ER retention motifrdquo European Journalof Cell Biology vol 61 no 1 pp 1ndash9 1993

[122] L P Jackson M Lewis H M Kent et al ldquoMolecular basis forrecognition of dilysine trafficking motifs by COPIrdquo Develop-mental Cell vol 23 pp 1ndash8 2012

[123] W Nickel K Sohn C Bunning and F T Wieland ldquop23 Amajor COPI-vesicle membrane protein constitutively cyclesthrough the early secretory pathwayrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 94 no21 pp 11393ndash11398 1997

[124] J C Semenza K G Hardwick N Dean and H R BPelham ldquoERD2 a yeast gene required for the receptor-mediatedretrieval of luminal ER proteins from the secretory pathwayrdquoCell vol 61 no 7 pp 1349ndash1357 1990

[125] I Majoul M Straub S W Hell R Duden and H D SolingldquoKDEL-cargo regulates interactions between proteins involvedin COPI vesicle traffic measurements in living cells usingFRETrdquo Developmental Cell vol 1 no 1 pp 139ndash153 2001

[126] B S Glick ldquoOrganization of the Golgi apparatusrdquo CurrentOpinion in Cell Biology vol 12 no 4 pp 450ndash456 2000

[127] R Blum D J Stephens and I Schulz ldquoLumenal targeted GFPused as a marker of soluble cargo visualises rapid ERGIC toGolgi traffic by a tubulo-vesicular networkrdquo Journal of CellScience vol 113 no 18 pp 3151ndash3159 2000

[128] J C Simpson T Nilsson and R Pepperkok ldquoBiogenesis oftubular ER-to-golgi transport intermediatesrdquoMolecular Biologyof the Cell vol 17 no 2 pp 723ndash737 2006

[129] K Hirschberg C M Miller J Ellenberg et al ldquoKinetic analysisof secretory protein traffic and characterization of Golgi toplasma membrane transport intermediates in living cellsrdquoJournal of Cell Biology vol 143 no 6 pp 1485ndash1503 1998

[130] D Toomre P Keller JWhite J C Olivo and K Simons ldquoDual-color visualization of trans-Golgi network to plasmamembranetraffic alongmicrotubules in living cellsrdquo Journal of Cell Sciencevol 112 no 1 pp 21ndash33 1999

[131] L Hermo A Rambourg and Y Clermont ldquoThree-dimensionalarchitecture of the cortical region of the Golgi apparatus in ratspermatidsrdquo American Journal of Anatomy vol 157 no 4 pp357ndash373 1980

[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

10 ISRN Cell Biology

[5] C Wilson R Venditti L R Rega A Colanzi G DrsquoAngeloandM A De ldquoThe Golgi apparatus an organelle with multiplecomplex functionsrdquo Biochemical Journal vol 433 no 1 pp 1ndash92011

[6] J Lippincott-Schwartz E Snapp and A Kemvorthy ldquoStudyingprotein dynamics in living cellsrdquoNature Reviews Molecular CellBiology vol 2 no 6 pp 444ndash456 2001

[7] G Perinetti T Muller A Spaar R Polishchuk A Luini andA Egner ldquoCorrelation of 4Pi and electron microscopy to studytransport through single golgi stacks in living cells with superresolutionrdquo Traffic vol 10 no 4 pp 379ndash391 2009

[8] J Lippincott-Schwartz ldquoEmerging in vivo analyses of cellfunction using fluorescence imagingrdquo Annual Review of Bio-chemistry vol 80 pp 327ndash332 2011

[9] A Gilchrist C E Au J Hiding et al ldquoQuantitative proteomicsanalysis of the secretory pathwayrdquo Cell vol 127 no 6 pp 1265ndash1281 2006

[10] J Gannon J J Bergeron and T Nilsson ldquoGolgi and relatedvesicle proteomics simplify to identifyrdquo Cold Spring HarborPerspectives in Biology vol 3 no 12 2011

[11] F Bard L Casano A Mallabiabarrena et al ldquoFunctionalgenomics reveals genes involved in protein secretion and Golgiorganizationrdquo Nature vol 439 pp 604ndash607 2006

[12] J W Slot and H J Geuze ldquoImmunoelectron microscopicexploration of theGolgi complexrdquo Journal ofHistochemistry andCytochemistry vol 31 no 8 pp 1049ndash1056 1983

[13] D ZeuschnerW J C Geerts E vanDonselaar et al ldquoImmuno-electron tomography of ER exit sites reveals the existence of freeCOPII-coated transport carriersrdquoNature Cell Biology vol 8 no4 pp 377ndash383 2006

[14] R S Polishchuk E V Polishchuk P Marra et al ldquoCorrelativelight-electron microscopy reveals the tubular-saccular ultra-structure of carriers operating between Golgi apparatus andplasma membranerdquo Journal of Cell Biology vol 148 no 1 pp45ndash58 2000

[15] B S Donohoe S Mogelsvang and L A Staehelin ldquoElectrontomography of ER Golgi and related membrane systemsrdquoMethods vol 39 no 2 pp 154ndash162 2006

[16] N K Gonatas A Stieber and J O Gonatas ldquoFragmentationof the Golgi apparatus in neurodegenerative diseases and celldeathrdquo Journal of the Neurological Sciences vol 246 no 1-2 pp21ndash30 2006

[17] M C Derby and P A Gleeson ldquoNew insights into membranetrafficking and protein sortingrdquo International Review of Cytol-ogy vol 261 pp 47ndash116 2007

[18] A A Mironov and M Pavelka The Golgi Apparatus State ofthe Art 110 Years after Camillo Golgirsquos Discovery Springer WienNewYork NY USA 2008

[19] E Papanikou and B S Glick ldquoThe yeast Golgi apparatusinsights and mysteriesrdquo FEBS Letters vol 583 no 23 pp 3746ndash3751 2009

[20] J H Wei and J Seemann ldquoMitotic division of the mammalianGolgi apparatusrdquo Seminars in Cell and Developmental Biologyvol 20 no 7 pp 810ndash816 2009

[21] M Anitei and B Hoflack ldquoExit from the trans-Golgi networkfrom molecules to mechanismsrdquo Current Opinion in Cell Biol-ogy vol 23 no 4 pp 443ndash451 2011

[22] J Klumperman ldquoArchitecture of the mammalian Golgirdquo ColdSpring Harbor Perspectives in Biology vol 3 no 7 Article IDa005181 2011

[23] YWang and J Seemann ldquoGolgi biogenesisrdquoCold Spring HarborPerspectives in Biology vol 3 no 10 Article ID a005330 2011

[24] K W Moremen M Tiemeyer and A V Nairn ldquoVertebrateprotein glycosylation diversity synthesis and functionrdquoNatureReviews Molecular Cell Biology vol 13 pp 448ndash462 2012

[25] A J Dalton and M D Felix ldquoA comparative study of the Golgicomplexrdquo The Journal of Biophysical and Biochemical Cytologyvol 2 no 4 pp 79ndash84 1956

[26] A Rambourg Y Clermont and A Marraud ldquoThree dimen-sional structure of the osmium impregnated Golgi apparatus asseen in the high voltage electronmicroscoperdquoAmerican Journalof Anatomy vol 140 no 1 pp 27ndash46 1974

[27] A Rambourg Y Clermont and L Hermo ldquoThree-dimensionalarchitecture of the Golgi apparatus in Sertoli cells of the ratrdquoAmerican Journal of Anatomy vol 154 no 4 pp 455ndash476 1979

[28] M S Ladinsky D NMastronarde J RMcIntosh K E Howelland L A Staehelin ldquoGolgi structure in three dimensionsfunctional insights from the normal rat kidney cellrdquo Journal ofCell Biology vol 144 no 6 pp 1135ndash1149 1999

[29] R S Taylor S M Jones R H Dahl M H Nordeen andK E Howell ldquoCharacterization of the Golgi complex clearedof proteins in transit and examination of calcium uptakeactivitiesrdquo Molecular Biology of the Cell vol 8 no 10 pp 1911ndash1931 1997

[30] MMWuM Grabe S Adams R Y Tsien H P HMoore andT E Machen ldquoMechanisms of pH regulation in the regulatedsecretory pathwayrdquo Journal of Biological Chemistry vol 276 no35 pp 33027ndash33035 2001

[31] J HWei and J Seemann ldquoUnraveling theGolgi ribbonrdquoTrafficvol 11 no 11 pp 1391ndash1400 2010

[32] A A Mironov and G V Beznoussenko ldquoMolecular mecha-nisms responsible for formation of Golgi ribbonrdquoHistology andHistopathology vol 26 no 1 pp 117ndash133 2011

[33] B Storrie JWhite S Rottger E H K Stelzer T Suganuma andT Nilsson ldquoRecycling of Golgi-resident glycosyltransferasesthrough the ER reveals a novel pathway and provides anexplanation for nocodazole-induced Golgi scatteringrdquo Journalof Cell Biology vol 143 no 6 pp 1505ndash1521 1998

[34] J Fan Z Hu L Zeng et al ldquoGolgi apparatus and neurode-generative diseasesrdquo International Journal of DevelopmentalNeuroscience vol 26 no 6 pp 523ndash534 2008

[35] Y Fujita EOhamaMTakatama S Al-Sarraj andKOkamotoldquoFragmentation of Golgi apparatus of nigral neurons with120572-synuclein-positive inclusions in patients with Parkinsonrsquosdiseaserdquo Acta Neuropathologica vol 112 no 3 pp 261ndash2652006

[36] G Thorne-Tjomsland M Dumontier and J C Jamiesonldquo3D topography of noncompact zone Golgi tubules in ratspermatids a computer-assisted serial section reconstructionstudyrdquoThe Anatomical Record vol 250 pp 381ndash396 1998

[37] A S Opat C Van Vliet and P A Gleeson ldquoTrafficking andlocalisation of residentGolgi glycosylation enzymesrdquoBiochimievol 83 no 8 pp 763ndash773 2001

[38] M G Farquhar and H P Hauri ldquoProtein sorting and vesiculartraffic in the Golgi apparatusrdquo inTheGolgi Apparatus E Bergerand J Roth Eds pp 63ndash128 Birkhauser Basel Switzerland1997

[39] G van Meer ldquoLipids of the Golgi membranerdquo Trends in CellBiology vol 8 no 1 pp 29ndash33 1998

[40] J C M Holthuis T Pomorski R J Raggers H Sprong andG Van Meer ldquoThe organizing potential of sphingolipids in

ISRN Cell Biology 11

intracellular membrane transportrdquo Physiological Reviews vol81 no 4 pp 1689ndash1723 2001

[41] D K Banfield ldquoMechanisms of protein retention in the GolgirdquoCold Spring Harbor Perspectives in Biology vol 3 Article IDa005264 2011

[42] D J Gill J Chia J Senewiratne and F Bard ldquoRegulation ofO-glycosylation through Golgi-to-ER relocation of initiationenzymesrdquo Journal of Cell Biology vol 189 no 5 pp 843ndash8582010

[43] A Sesso F Paulo de Faria E S M Iwamura and H Correa ldquoAthree-dimensional reconstruction study of the rough ER-Golgiinterface in serial thin sections of the pancreatic acinar cell ofthe ratrdquo Journal of Cell Science vol 107 no 3 pp 517ndash528 1994

[44] Y Clermont A Rambourg and L Hermo ldquoConnectionsbetween the various elements of the cis- and mid-compart-ments of the Golgi apparatus of early rat spermatidsrdquo Anatomi-cal Record vol 240 no 4 pp 469ndash480 1994

[45] A Rambourg and Y Clermont ldquoThree-dimensional structureof the Golgi apparatus in mammalian cellsrdquo in The GolgiApparatus E G Berger and J Roth Eds pp 37ndash61 BirkhauserBasel Switzerland 1997

[46] G Vivero-Salmeron J Ballesta and J A Martınez-MenarguezldquoHeterotypic tubular connections at the endoplasmic reticu-lum-Golgi complex interfacerdquo Histochemistry and Cell Biologyvol 130 pp 709ndash717 2008

[47] C vanVliet E CThomas AMerino-Trigo R D Teasdale andP A Gleeson ldquoIntracellular sorting and transport of proteinsrdquoProgress in Biophysics and Molecular Biology vol 83 no 1 pp1ndash45 2003

[48] G Griffiths S Pfeiffer K Simons and K Matlin ldquoExit of newlysynthesized membrane proteins from the trans cisterna of theGolgi complex to the plasmamembranerdquo Journal of Cell Biologyvol 101 no 3 pp 949ndash964 1985

[49] G Griffiths S D Fuller R BackMHollinshead S Pfeiffer andK Simons ldquoThe dynamic nature of the Golgi complexrdquo Journalof Cell Biology vol 108 no 2 pp 277ndash297 1989

[50] H J Geuze and D J Morre ldquoTrans-Golgi reticulumrdquo Journal ofElectron Microscopy Technique vol 17 no 1 pp 24ndash34 1991

[51] Y Clermont A Rambourg and L Hermo ldquoTrans-Golgi net-work (TGN) of different cell types three-dimensional structuralcharacteristics and variabilityrdquo Anatomical Record vol 242 no3 pp 289ndash301 1995

[52] R S Polishchuk andA AMironov ldquoStructural aspects of Golgifunctionrdquo Cellular andMolecular Life Sciences vol 61 no 2 pp146ndash158 2004

[53] P A Gleeson J G Lock M R Luke and J L Stow ldquoDomainsof the TGN coats tethers and G proteinsrdquo Traffic vol 5 no 5pp 315ndash326 2004

[54] F Bard and V Malhotra ldquoThe formation of TGN-to-plasma-membrane transport carriersrdquo Annual Review of Cell andDevelopmental Biology vol 22 pp 439ndash455 2006

[55] R D Klausner J G Donaldson and J Lippincott-SchwartzldquoBrefeldin A insights into the control of membrane traffic andorganelle structurerdquo Journal of Cell Biology vol 116 no 5 pp1071ndash1080 1992

[56] J Llopis J M McCaffery A Miyawaki M G Farquhar andR Y Tsien ldquoMeasurement of cytosolic mitochondrial andGolgi pH in single living cells with green fluorescent proteinsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 12 pp 6803ndash6808 1998

[57] H HMollenhauer andD J Morre ldquoThe tubular network of theGolgi apparatusrdquo Histochemistry and Cell Biology vol 109 no5-6 pp 533ndash543 1998

[58] L Orci A Perrelet and J E Rothman ldquoVesicles on stringsMorphological evidence for processive transport within theGolgi stackrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 95 no 5 pp 2279ndash2283 1998

[59] Y Xiang and Y Wang ldquoNew components of the Golgi matrixrdquoCell and Tissue Research vol 344 no 3 pp 365ndash379 2011

[60] N Nakamura C Rabouille R Watson et al ldquoCharacterizationof a cis-Golgi matrix protein GM130rdquo Journal of Cell Biologyvol 131 no 6 pp 1715ndash1726 1995

[61] P Slusarewicz T Nilsson N Hui R Watson and G WarrenldquoIsolation of amatrix that bindsmedial Golgi enzymesrdquo Journalof Cell Biology vol 124 no 4 pp 405ndash413 1994

[62] G Egea and R M Rios ldquoThe role of the cytoskeleton in thestructure and function of the Golgi apparatusrdquo in The GolgiApparatus A A Mironov and M Pavelka Eds pp 270ndash300Springer NewYork NY USA 2008

[63] M Lowe ldquoStructural organization of the Golgi apparatusrdquoCurrent Opinion in Cell Biology vol 23 no 1 pp 85ndash93 2011

[64] R M Rios and M Bornens ldquoThe Golgi apparatus at the cellcentrerdquoCurrent Opinion in Cell Biology vol 15 pp 60ndash66 2003

[65] S Yadav and A D Linstedt ldquoGolgi positioningrdquo Cold SpringHarbor Perspectives in Biology vol 3 pp 1ndash17 2011

[66] J K Burkhardt ldquoThe role of microtubule-based motor proteinsin maintaining the structure and function of the Golgi com-plexrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp 113ndash126 1998

[67] K Chabin-Brion J Marceiller F Perez et al ldquoThe Golgi com-plex is a microtubule-organizing organellerdquo Molecular Biologyof the Cell vol 12 no 7 pp 2047ndash2060 2001

[68] S Rivero J Cardenas M Bornens and R M Rios ldquoMicro-tubule nucleation at the cis-side of the golgi apparatus requiresAKAP450 and GM130rdquo The EMBO Journal vol 28 no 8 pp1016ndash1028 2009

[69] A Efimov A Kharitonov N Efimova et al ldquoAsymmetricCLASP-dependent nucleation of noncentrosomal microtubulesat the trans-Golgi Networkrdquo Developmental Cell vol 12 no 6pp 917ndash930 2007

[70] P M Miller A W Folkmann A R R Maia N EfimovaA Efimov and I Kaverina ldquoGolgi-derived CLASP-dependentmicrotubules control Golgi organization and polarized traffick-ing in motile cellsrdquo Nature Cell Biology vol 11 no 9 pp 1069ndash1080 2009

[71] F Valderrama A Luna T Babia et al ldquoThe Golgi-associatedCOPI-coated buds and vesicles contain 120573120574-actinrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 97 no 4 pp 1560ndash1565 2000

[72] G Egea F Lazaro-Dieguez and M Vilella ldquoActin dynamics atthe Golgi complex inmammalian cellsrdquoCurrent Opinion in CellBiology vol 18 pp 168ndash178 2006

[73] F Lazaro-Dieguez C Colonna M Cortegano M Calvo S EMartınez and G Egea ldquoVariable actin dynamics requirementfor the exit of different cargo from the trans-Golgi networkrdquoFEBS Letters vol 581 no 20 pp 3875ndash3881 2007

[74] F Valderrama J M Duran T Babia H Barth J Renau-Piqueras and G Egea ldquoActin microfilaments facilitate theretrogade transport from the Golgi complex to the endoplasmicreticulum in mammalian cellsrdquo Traffic vol 2 no 10 pp 717ndash726 2001

12 ISRN Cell Biology

[75] A Disanza and G Scita ldquoCytoskeletal regulation coordinatingactin and microtubule dynamics in membrane traffickingrdquoCurrent Biology vol 18 no 18 pp R873ndashR875 2008

[76] K G Campellone N J Webb E A Znameroski and M DWelch ldquoWHAMM is an Arp23 complex activator that bindsmicrotubules and functions in ER to golgi transportrdquo Cell vol134 no 1 pp 148ndash161 2008

[77] Q T Shen P P Hsiue C V Sindelar M D Welch KG Campellone and H W Wang ldquoStructural insights intoWHAMM-mediated cytoskeletal coordination during mem-brane remodelingrdquoThe Journal of Cell Biology vol 199 pp 111ndash124 2012

[78] T F Roth and K R Porter ldquoYolk protein uptake in the oocyteof the mosquito Aedes aegypti Lrdquo The Journal of Cell Biologyvol 20 pp 313ndash332 1964

[79] B M F Pearse ldquoClathrin a unique protein associated withintracellular transfer of membrane by coated vesiclesrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 73 no 4 pp 1255ndash1259 1976

[80] A Oprins R Duden T E Kreis H J Geuze and J W Slotldquo120573-COP localizes mainly to the cis-Golgi side in exocrinepancreasrdquo Journal of Cell Biology vol 121 no 1 pp 49ndash60 1993

[81] B M F Pearse and M S Robinson ldquoClathrin adaptors andsortingrdquo Annual Review of Cell Biology vol 6 pp 151ndash171 1990

[82] T Braulke and J S Bonifacino ldquoSorting of lysosomal proteinsrdquoBiochimica et BiophysicaActa vol 1793 no 4 pp 605ndash614 2009

[83] T Kirchhausen ldquoClathrinrdquo Annual Review of Biochemistry vol69 pp 699ndash727 2000

[84] E Rodriguez-Boulan and A Musch ldquoProtein sorting in theGolgi complex shifting paradigmsrdquo Biochimica et BiophysicaActa vol 1744 no 3 pp 455ndash464 2005

[85] M A McNiven H Cao K R Pitts and Y Yoon ldquoThe dynaminfamily of mechanoenzymes pinching in new placesrdquo Trends inBiochemical Sciences vol 25 no 3 pp 115ndash120 2000

[86] E Eisenberg and L E Greene ldquoMultiple roles of auxilin andHsc70 in clathrin-mediated endocytosisrdquo Traffic vol 8 no 6pp 640ndash646 2007

[87] C Barlowe L Orci T Yeung et al ldquoCOPII a membrane coatformed by sec proteins that drive vesicle budding from theendoplasmic reticulumrdquo Cell vol 77 no 6 pp 895ndash907 1994

[88] L C Bickford E Mossessova and J Goldberg ldquoA structuralview of the COPII vesicle coatrdquo Current Opinion in StructuralBiology vol 14 no 2 pp 147ndash153 2004

[89] D Jensen and R Schekman ldquoCOPII-mediated vesicle forma-tion at a glancerdquo Journal of Cell Science vol 124 no 1 pp 1ndash42011

[90] T Kirchhausen ldquoMaking COPII coatsrdquo Cell vol 129 no 7 pp1251ndash1252 2007

[91] C Barlowe ldquoCOPII and selective export from the endoplasmicreticulumrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp67ndash76 1998

[92] J A Martınez-Menarguez H J Geuze J W Slot and JKlumperman ldquoVesicular tubular clusters between the ER andGolgi mediate concentration of soluble secretory proteins byexclusion fromCOPI-coated vesiclesrdquoCell vol 98 no 1 pp 81ndash90 1999

[93] K Saito M Chen F Bard et al ldquoTANGO1 facilitates cargoloading at endoplasmic reticulum exit sitesrdquo Cell vol 136 no5 pp 891ndash902 2009

[94] L Jin K B Pahuja K E Wickliffe et al ldquoUbiquitin-dependentregulation of COPII coat size and functionrdquo Nature vol 482pp 495ndash500 2012

[95] H P Hauri and A Schweizer ldquoThe endoplasmic reticulum-Golgi intermediate compartmentrdquo Current Opinion in CellBiology vol 4 no 4 pp 600ndash608 1992

[96] S I Bannykh T Rowe and W E Balch ldquoThe organizationof endoplasmic reticulum export complexesrdquo Journal of CellBiology vol 135 no 1 pp 19ndash35 1996

[97] J Saraste and E Kuismanen ldquoPre- and post-Golgi vacuolesoperate in the transport of Semliki Forest virus membraneglycoproteins to the cell surfacerdquo Cell vol 38 no 2 pp 535ndash549 1984

[98] A Schweizer J A M Fransen K Matter T E Kreis L GinselandH PHauri ldquoIdentification of an intermediate compartmentinvolved in protein transport from endoplasmic reticulum toGolgi apparatusrdquo European Journal of Cell Biology vol 53 no 2pp 185ndash196 1990

[99] H Ben-Takaya K Miura R Pepperkok and H P Hauri ldquoLiveimaging of bidirectional traffic from the ERGICrdquo Journal of CellScience vol 118 no 2 pp 357ndash367 2005

[100] Y C Zhang Y Zhou C Z Yang and D S Xiong ldquoA reviewof ERGIC-53 its structure functions regulation and relationswith diseasesrdquo Histology and Histopathology vol 24 no 9 pp1193ndash1204 2009

[101] J F Presley N B Cole T A Schroer K Hirschberg K JM Zaal and J Lippincott-Schwartz ldquoER-to-Golgi transportvisualized in living cellsrdquo Nature vol 389 no 6646 pp 81ndash851997

[102] J A Martınez-Menarguez H J Geuze and J Ballesta ldquoIdenti-fication of two types of beta-COP vesicles in the Golgi complexof rat spermatidsrdquo European Journal of Cell Biology vol 71 pp137ndash143 1996

[103] J Lippincott-Schwartz J G Donaldson A Schweizer et alldquoMicrotubule-dependent retrograde transport of proteins intothe ER in the presence of brefeldin A suggests an ER recyclingpathwayrdquo Cell vol 60 no 5 pp 821ndash836 1990

[104] A Girod B Storrie J C Simpson et al ldquoEvidence for a COP-I-independent transport route from the Golgi complex to theendoplasmic reticulumrdquo Nature Cell Biology vol 1 no 7 pp423ndash430 1999

[105] V Popoff F Adolf B Brugger and F Wieland ldquoCOPI buddingwithin the Golgi stackrdquo Cold Spring Harbor Perspectives inBiology vol 3 Article ID a005231 2011

[106] J Moelleken J Malsam M J Betts et al ldquoDifferential localiza-tion of coatomer complex isoforms within the Golgi apparatusrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 104 no 11 pp 4425ndash4430 2007

[107] L Orci B S Glick and J E Rothman ldquoA new type of coatedvesicular carrier that appears not to contain clathrin its possiblerole in protein transport within theGolgi stackrdquoCell vol 46 no2 pp 171ndash184 1986

[108] V Malhotra T Serafini L Orci J C Shepherd and J ERothman ldquoPurification of a novel class of coated vesiclesmediating biosynthetic protein transport through the Golgistackrdquo Cell vol 58 no 2 pp 329ndash336 1989

[109] M G Waters T Serafini and J E Rothman ldquolsquoCoatomerrsquo acytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesiclesrdquo Nature vol 349 no 6306 pp248ndash251 1991

[110] T Serafini L Orci M Amherdt M Brunner R A Kahn andJ E Rothman ldquoADP-ribosylation factor is a subunit of the coatof Golgi-derived COP-coated vesicles a novel role for a GTP-binding proteinrdquo Cell vol 67 no 2 pp 239ndash253 1991

ISRN Cell Biology 13

[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

[112] K Kawamoto Y Yoshida H Tamaki et al ldquoGBF1 a guaninenucleotide exchange factor for ADP-ribosylation factors islocalized to the cis-Golgi and involved inmembrane associationof the COPI coatrdquo Traffic vol 3 no 7 pp 483ndash495 2002

[113] R Garcıa-Mata T Szul C Alvarez and E Sztul ldquoADP-ribosylation factorCOPI-dependent events at the endoplas-mic reticulum-Golgi interface are regulated by the guaninenucleotide exchange factor GBF1rdquoMolecular Biology of the Cellvol 14 no 6 pp 2250ndash2261 2003

[114] H Inoue and P A Randazzo ldquoArf GAPs and their interactingproteinsrdquo Traffic vol 8 no 11 pp 1465ndash1475 2007

[115] G Tanigawa L Orci M Amherdt M Ravazzola J B Helmsand J E Rothman ldquoHydrolysis of bound GTP by ARF proteintriggers uncoating of Golgi- derived COP-coated vesiclesrdquoJournal of Cell Biology vol 123 no 6 pp 1365ndash1371 1993

[116] Y Shiba and P A Randazzo ldquoArfGAP1 function in COPImediated membrane traffic currently debated models andcomparison to other coat-binding ArfGAPsrdquo Histology andHistopathology vol 27 pp 1143ndash1153 2012

[117] J Bigay P Gounon S Roblneau and B Antonny ldquoLipidpacking sensed by ArfGAP1 couples COPI coat disassembly tomembrane bilayer curvaturerdquo Nature vol 426 no 6966 pp563ndash566 2003

[118] W Nickel J Malsam K Gorgas et al ldquoUptake by COPI-coatedvesicles of both anterograde and retrograde cargo is inhibitedby GTP120574S in vitrordquo Journal of Cell Science vol 111 no 20 pp3081ndash3090 1998

[119] R Beck M Rawet F T Wieland and D Cassel ldquoThe COPIsystemmolecularmechanisms and functionrdquo FEBS Letters vol583 pp 2701ndash2709 2009

[120] F Letourneur E C Gaynor S Hennecke et al ldquoCoatomeris essential for retrieval of dilysine-tagged proteins to theendoplasmic reticulumrdquo Cell vol 79 no 7 pp 1199ndash1207 1994

[121] R Schindler C Itin M Zerial F Lottspeich and H P HaurildquoERGIC-53 a membrane protein of the ER-Golgi intermediatecompartment carries an ER retention motifrdquo European Journalof Cell Biology vol 61 no 1 pp 1ndash9 1993

[122] L P Jackson M Lewis H M Kent et al ldquoMolecular basis forrecognition of dilysine trafficking motifs by COPIrdquo Develop-mental Cell vol 23 pp 1ndash8 2012

[123] W Nickel K Sohn C Bunning and F T Wieland ldquop23 Amajor COPI-vesicle membrane protein constitutively cyclesthrough the early secretory pathwayrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 94 no21 pp 11393ndash11398 1997

[124] J C Semenza K G Hardwick N Dean and H R BPelham ldquoERD2 a yeast gene required for the receptor-mediatedretrieval of luminal ER proteins from the secretory pathwayrdquoCell vol 61 no 7 pp 1349ndash1357 1990

[125] I Majoul M Straub S W Hell R Duden and H D SolingldquoKDEL-cargo regulates interactions between proteins involvedin COPI vesicle traffic measurements in living cells usingFRETrdquo Developmental Cell vol 1 no 1 pp 139ndash153 2001

[126] B S Glick ldquoOrganization of the Golgi apparatusrdquo CurrentOpinion in Cell Biology vol 12 no 4 pp 450ndash456 2000

[127] R Blum D J Stephens and I Schulz ldquoLumenal targeted GFPused as a marker of soluble cargo visualises rapid ERGIC toGolgi traffic by a tubulo-vesicular networkrdquo Journal of CellScience vol 113 no 18 pp 3151ndash3159 2000

[128] J C Simpson T Nilsson and R Pepperkok ldquoBiogenesis oftubular ER-to-golgi transport intermediatesrdquoMolecular Biologyof the Cell vol 17 no 2 pp 723ndash737 2006

[129] K Hirschberg C M Miller J Ellenberg et al ldquoKinetic analysisof secretory protein traffic and characterization of Golgi toplasma membrane transport intermediates in living cellsrdquoJournal of Cell Biology vol 143 no 6 pp 1485ndash1503 1998

[130] D Toomre P Keller JWhite J C Olivo and K Simons ldquoDual-color visualization of trans-Golgi network to plasmamembranetraffic alongmicrotubules in living cellsrdquo Journal of Cell Sciencevol 112 no 1 pp 21ndash33 1999

[131] L Hermo A Rambourg and Y Clermont ldquoThree-dimensionalarchitecture of the cortical region of the Golgi apparatus in ratspermatidsrdquo American Journal of Anatomy vol 157 no 4 pp357ndash373 1980

[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

ISRN Cell Biology 11

intracellular membrane transportrdquo Physiological Reviews vol81 no 4 pp 1689ndash1723 2001

[41] D K Banfield ldquoMechanisms of protein retention in the GolgirdquoCold Spring Harbor Perspectives in Biology vol 3 Article IDa005264 2011

[42] D J Gill J Chia J Senewiratne and F Bard ldquoRegulation ofO-glycosylation through Golgi-to-ER relocation of initiationenzymesrdquo Journal of Cell Biology vol 189 no 5 pp 843ndash8582010

[43] A Sesso F Paulo de Faria E S M Iwamura and H Correa ldquoAthree-dimensional reconstruction study of the rough ER-Golgiinterface in serial thin sections of the pancreatic acinar cell ofthe ratrdquo Journal of Cell Science vol 107 no 3 pp 517ndash528 1994

[44] Y Clermont A Rambourg and L Hermo ldquoConnectionsbetween the various elements of the cis- and mid-compart-ments of the Golgi apparatus of early rat spermatidsrdquo Anatomi-cal Record vol 240 no 4 pp 469ndash480 1994

[45] A Rambourg and Y Clermont ldquoThree-dimensional structureof the Golgi apparatus in mammalian cellsrdquo in The GolgiApparatus E G Berger and J Roth Eds pp 37ndash61 BirkhauserBasel Switzerland 1997

[46] G Vivero-Salmeron J Ballesta and J A Martınez-MenarguezldquoHeterotypic tubular connections at the endoplasmic reticu-lum-Golgi complex interfacerdquo Histochemistry and Cell Biologyvol 130 pp 709ndash717 2008

[47] C vanVliet E CThomas AMerino-Trigo R D Teasdale andP A Gleeson ldquoIntracellular sorting and transport of proteinsrdquoProgress in Biophysics and Molecular Biology vol 83 no 1 pp1ndash45 2003

[48] G Griffiths S Pfeiffer K Simons and K Matlin ldquoExit of newlysynthesized membrane proteins from the trans cisterna of theGolgi complex to the plasmamembranerdquo Journal of Cell Biologyvol 101 no 3 pp 949ndash964 1985

[49] G Griffiths S D Fuller R BackMHollinshead S Pfeiffer andK Simons ldquoThe dynamic nature of the Golgi complexrdquo Journalof Cell Biology vol 108 no 2 pp 277ndash297 1989

[50] H J Geuze and D J Morre ldquoTrans-Golgi reticulumrdquo Journal ofElectron Microscopy Technique vol 17 no 1 pp 24ndash34 1991

[51] Y Clermont A Rambourg and L Hermo ldquoTrans-Golgi net-work (TGN) of different cell types three-dimensional structuralcharacteristics and variabilityrdquo Anatomical Record vol 242 no3 pp 289ndash301 1995

[52] R S Polishchuk andA AMironov ldquoStructural aspects of Golgifunctionrdquo Cellular andMolecular Life Sciences vol 61 no 2 pp146ndash158 2004

[53] P A Gleeson J G Lock M R Luke and J L Stow ldquoDomainsof the TGN coats tethers and G proteinsrdquo Traffic vol 5 no 5pp 315ndash326 2004

[54] F Bard and V Malhotra ldquoThe formation of TGN-to-plasma-membrane transport carriersrdquo Annual Review of Cell andDevelopmental Biology vol 22 pp 439ndash455 2006

[55] R D Klausner J G Donaldson and J Lippincott-SchwartzldquoBrefeldin A insights into the control of membrane traffic andorganelle structurerdquo Journal of Cell Biology vol 116 no 5 pp1071ndash1080 1992

[56] J Llopis J M McCaffery A Miyawaki M G Farquhar andR Y Tsien ldquoMeasurement of cytosolic mitochondrial andGolgi pH in single living cells with green fluorescent proteinsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 12 pp 6803ndash6808 1998

[57] H HMollenhauer andD J Morre ldquoThe tubular network of theGolgi apparatusrdquo Histochemistry and Cell Biology vol 109 no5-6 pp 533ndash543 1998

[58] L Orci A Perrelet and J E Rothman ldquoVesicles on stringsMorphological evidence for processive transport within theGolgi stackrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 95 no 5 pp 2279ndash2283 1998

[59] Y Xiang and Y Wang ldquoNew components of the Golgi matrixrdquoCell and Tissue Research vol 344 no 3 pp 365ndash379 2011

[60] N Nakamura C Rabouille R Watson et al ldquoCharacterizationof a cis-Golgi matrix protein GM130rdquo Journal of Cell Biologyvol 131 no 6 pp 1715ndash1726 1995

[61] P Slusarewicz T Nilsson N Hui R Watson and G WarrenldquoIsolation of amatrix that bindsmedial Golgi enzymesrdquo Journalof Cell Biology vol 124 no 4 pp 405ndash413 1994

[62] G Egea and R M Rios ldquoThe role of the cytoskeleton in thestructure and function of the Golgi apparatusrdquo in The GolgiApparatus A A Mironov and M Pavelka Eds pp 270ndash300Springer NewYork NY USA 2008

[63] M Lowe ldquoStructural organization of the Golgi apparatusrdquoCurrent Opinion in Cell Biology vol 23 no 1 pp 85ndash93 2011

[64] R M Rios and M Bornens ldquoThe Golgi apparatus at the cellcentrerdquoCurrent Opinion in Cell Biology vol 15 pp 60ndash66 2003

[65] S Yadav and A D Linstedt ldquoGolgi positioningrdquo Cold SpringHarbor Perspectives in Biology vol 3 pp 1ndash17 2011

[66] J K Burkhardt ldquoThe role of microtubule-based motor proteinsin maintaining the structure and function of the Golgi com-plexrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp 113ndash126 1998

[67] K Chabin-Brion J Marceiller F Perez et al ldquoThe Golgi com-plex is a microtubule-organizing organellerdquo Molecular Biologyof the Cell vol 12 no 7 pp 2047ndash2060 2001

[68] S Rivero J Cardenas M Bornens and R M Rios ldquoMicro-tubule nucleation at the cis-side of the golgi apparatus requiresAKAP450 and GM130rdquo The EMBO Journal vol 28 no 8 pp1016ndash1028 2009

[69] A Efimov A Kharitonov N Efimova et al ldquoAsymmetricCLASP-dependent nucleation of noncentrosomal microtubulesat the trans-Golgi Networkrdquo Developmental Cell vol 12 no 6pp 917ndash930 2007

[70] P M Miller A W Folkmann A R R Maia N EfimovaA Efimov and I Kaverina ldquoGolgi-derived CLASP-dependentmicrotubules control Golgi organization and polarized traffick-ing in motile cellsrdquo Nature Cell Biology vol 11 no 9 pp 1069ndash1080 2009

[71] F Valderrama A Luna T Babia et al ldquoThe Golgi-associatedCOPI-coated buds and vesicles contain 120573120574-actinrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 97 no 4 pp 1560ndash1565 2000

[72] G Egea F Lazaro-Dieguez and M Vilella ldquoActin dynamics atthe Golgi complex inmammalian cellsrdquoCurrent Opinion in CellBiology vol 18 pp 168ndash178 2006

[73] F Lazaro-Dieguez C Colonna M Cortegano M Calvo S EMartınez and G Egea ldquoVariable actin dynamics requirementfor the exit of different cargo from the trans-Golgi networkrdquoFEBS Letters vol 581 no 20 pp 3875ndash3881 2007

[74] F Valderrama J M Duran T Babia H Barth J Renau-Piqueras and G Egea ldquoActin microfilaments facilitate theretrogade transport from the Golgi complex to the endoplasmicreticulum in mammalian cellsrdquo Traffic vol 2 no 10 pp 717ndash726 2001

12 ISRN Cell Biology

[75] A Disanza and G Scita ldquoCytoskeletal regulation coordinatingactin and microtubule dynamics in membrane traffickingrdquoCurrent Biology vol 18 no 18 pp R873ndashR875 2008

[76] K G Campellone N J Webb E A Znameroski and M DWelch ldquoWHAMM is an Arp23 complex activator that bindsmicrotubules and functions in ER to golgi transportrdquo Cell vol134 no 1 pp 148ndash161 2008

[77] Q T Shen P P Hsiue C V Sindelar M D Welch KG Campellone and H W Wang ldquoStructural insights intoWHAMM-mediated cytoskeletal coordination during mem-brane remodelingrdquoThe Journal of Cell Biology vol 199 pp 111ndash124 2012

[78] T F Roth and K R Porter ldquoYolk protein uptake in the oocyteof the mosquito Aedes aegypti Lrdquo The Journal of Cell Biologyvol 20 pp 313ndash332 1964

[79] B M F Pearse ldquoClathrin a unique protein associated withintracellular transfer of membrane by coated vesiclesrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 73 no 4 pp 1255ndash1259 1976

[80] A Oprins R Duden T E Kreis H J Geuze and J W Slotldquo120573-COP localizes mainly to the cis-Golgi side in exocrinepancreasrdquo Journal of Cell Biology vol 121 no 1 pp 49ndash60 1993

[81] B M F Pearse and M S Robinson ldquoClathrin adaptors andsortingrdquo Annual Review of Cell Biology vol 6 pp 151ndash171 1990

[82] T Braulke and J S Bonifacino ldquoSorting of lysosomal proteinsrdquoBiochimica et BiophysicaActa vol 1793 no 4 pp 605ndash614 2009

[83] T Kirchhausen ldquoClathrinrdquo Annual Review of Biochemistry vol69 pp 699ndash727 2000

[84] E Rodriguez-Boulan and A Musch ldquoProtein sorting in theGolgi complex shifting paradigmsrdquo Biochimica et BiophysicaActa vol 1744 no 3 pp 455ndash464 2005

[85] M A McNiven H Cao K R Pitts and Y Yoon ldquoThe dynaminfamily of mechanoenzymes pinching in new placesrdquo Trends inBiochemical Sciences vol 25 no 3 pp 115ndash120 2000

[86] E Eisenberg and L E Greene ldquoMultiple roles of auxilin andHsc70 in clathrin-mediated endocytosisrdquo Traffic vol 8 no 6pp 640ndash646 2007

[87] C Barlowe L Orci T Yeung et al ldquoCOPII a membrane coatformed by sec proteins that drive vesicle budding from theendoplasmic reticulumrdquo Cell vol 77 no 6 pp 895ndash907 1994

[88] L C Bickford E Mossessova and J Goldberg ldquoA structuralview of the COPII vesicle coatrdquo Current Opinion in StructuralBiology vol 14 no 2 pp 147ndash153 2004

[89] D Jensen and R Schekman ldquoCOPII-mediated vesicle forma-tion at a glancerdquo Journal of Cell Science vol 124 no 1 pp 1ndash42011

[90] T Kirchhausen ldquoMaking COPII coatsrdquo Cell vol 129 no 7 pp1251ndash1252 2007

[91] C Barlowe ldquoCOPII and selective export from the endoplasmicreticulumrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp67ndash76 1998

[92] J A Martınez-Menarguez H J Geuze J W Slot and JKlumperman ldquoVesicular tubular clusters between the ER andGolgi mediate concentration of soluble secretory proteins byexclusion fromCOPI-coated vesiclesrdquoCell vol 98 no 1 pp 81ndash90 1999

[93] K Saito M Chen F Bard et al ldquoTANGO1 facilitates cargoloading at endoplasmic reticulum exit sitesrdquo Cell vol 136 no5 pp 891ndash902 2009

[94] L Jin K B Pahuja K E Wickliffe et al ldquoUbiquitin-dependentregulation of COPII coat size and functionrdquo Nature vol 482pp 495ndash500 2012

[95] H P Hauri and A Schweizer ldquoThe endoplasmic reticulum-Golgi intermediate compartmentrdquo Current Opinion in CellBiology vol 4 no 4 pp 600ndash608 1992

[96] S I Bannykh T Rowe and W E Balch ldquoThe organizationof endoplasmic reticulum export complexesrdquo Journal of CellBiology vol 135 no 1 pp 19ndash35 1996

[97] J Saraste and E Kuismanen ldquoPre- and post-Golgi vacuolesoperate in the transport of Semliki Forest virus membraneglycoproteins to the cell surfacerdquo Cell vol 38 no 2 pp 535ndash549 1984

[98] A Schweizer J A M Fransen K Matter T E Kreis L GinselandH PHauri ldquoIdentification of an intermediate compartmentinvolved in protein transport from endoplasmic reticulum toGolgi apparatusrdquo European Journal of Cell Biology vol 53 no 2pp 185ndash196 1990

[99] H Ben-Takaya K Miura R Pepperkok and H P Hauri ldquoLiveimaging of bidirectional traffic from the ERGICrdquo Journal of CellScience vol 118 no 2 pp 357ndash367 2005

[100] Y C Zhang Y Zhou C Z Yang and D S Xiong ldquoA reviewof ERGIC-53 its structure functions regulation and relationswith diseasesrdquo Histology and Histopathology vol 24 no 9 pp1193ndash1204 2009

[101] J F Presley N B Cole T A Schroer K Hirschberg K JM Zaal and J Lippincott-Schwartz ldquoER-to-Golgi transportvisualized in living cellsrdquo Nature vol 389 no 6646 pp 81ndash851997

[102] J A Martınez-Menarguez H J Geuze and J Ballesta ldquoIdenti-fication of two types of beta-COP vesicles in the Golgi complexof rat spermatidsrdquo European Journal of Cell Biology vol 71 pp137ndash143 1996

[103] J Lippincott-Schwartz J G Donaldson A Schweizer et alldquoMicrotubule-dependent retrograde transport of proteins intothe ER in the presence of brefeldin A suggests an ER recyclingpathwayrdquo Cell vol 60 no 5 pp 821ndash836 1990

[104] A Girod B Storrie J C Simpson et al ldquoEvidence for a COP-I-independent transport route from the Golgi complex to theendoplasmic reticulumrdquo Nature Cell Biology vol 1 no 7 pp423ndash430 1999

[105] V Popoff F Adolf B Brugger and F Wieland ldquoCOPI buddingwithin the Golgi stackrdquo Cold Spring Harbor Perspectives inBiology vol 3 Article ID a005231 2011

[106] J Moelleken J Malsam M J Betts et al ldquoDifferential localiza-tion of coatomer complex isoforms within the Golgi apparatusrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 104 no 11 pp 4425ndash4430 2007

[107] L Orci B S Glick and J E Rothman ldquoA new type of coatedvesicular carrier that appears not to contain clathrin its possiblerole in protein transport within theGolgi stackrdquoCell vol 46 no2 pp 171ndash184 1986

[108] V Malhotra T Serafini L Orci J C Shepherd and J ERothman ldquoPurification of a novel class of coated vesiclesmediating biosynthetic protein transport through the Golgistackrdquo Cell vol 58 no 2 pp 329ndash336 1989

[109] M G Waters T Serafini and J E Rothman ldquolsquoCoatomerrsquo acytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesiclesrdquo Nature vol 349 no 6306 pp248ndash251 1991

[110] T Serafini L Orci M Amherdt M Brunner R A Kahn andJ E Rothman ldquoADP-ribosylation factor is a subunit of the coatof Golgi-derived COP-coated vesicles a novel role for a GTP-binding proteinrdquo Cell vol 67 no 2 pp 239ndash253 1991

ISRN Cell Biology 13

[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

[112] K Kawamoto Y Yoshida H Tamaki et al ldquoGBF1 a guaninenucleotide exchange factor for ADP-ribosylation factors islocalized to the cis-Golgi and involved inmembrane associationof the COPI coatrdquo Traffic vol 3 no 7 pp 483ndash495 2002

[113] R Garcıa-Mata T Szul C Alvarez and E Sztul ldquoADP-ribosylation factorCOPI-dependent events at the endoplas-mic reticulum-Golgi interface are regulated by the guaninenucleotide exchange factor GBF1rdquoMolecular Biology of the Cellvol 14 no 6 pp 2250ndash2261 2003

[114] H Inoue and P A Randazzo ldquoArf GAPs and their interactingproteinsrdquo Traffic vol 8 no 11 pp 1465ndash1475 2007

[115] G Tanigawa L Orci M Amherdt M Ravazzola J B Helmsand J E Rothman ldquoHydrolysis of bound GTP by ARF proteintriggers uncoating of Golgi- derived COP-coated vesiclesrdquoJournal of Cell Biology vol 123 no 6 pp 1365ndash1371 1993

[116] Y Shiba and P A Randazzo ldquoArfGAP1 function in COPImediated membrane traffic currently debated models andcomparison to other coat-binding ArfGAPsrdquo Histology andHistopathology vol 27 pp 1143ndash1153 2012

[117] J Bigay P Gounon S Roblneau and B Antonny ldquoLipidpacking sensed by ArfGAP1 couples COPI coat disassembly tomembrane bilayer curvaturerdquo Nature vol 426 no 6966 pp563ndash566 2003

[118] W Nickel J Malsam K Gorgas et al ldquoUptake by COPI-coatedvesicles of both anterograde and retrograde cargo is inhibitedby GTP120574S in vitrordquo Journal of Cell Science vol 111 no 20 pp3081ndash3090 1998

[119] R Beck M Rawet F T Wieland and D Cassel ldquoThe COPIsystemmolecularmechanisms and functionrdquo FEBS Letters vol583 pp 2701ndash2709 2009

[120] F Letourneur E C Gaynor S Hennecke et al ldquoCoatomeris essential for retrieval of dilysine-tagged proteins to theendoplasmic reticulumrdquo Cell vol 79 no 7 pp 1199ndash1207 1994

[121] R Schindler C Itin M Zerial F Lottspeich and H P HaurildquoERGIC-53 a membrane protein of the ER-Golgi intermediatecompartment carries an ER retention motifrdquo European Journalof Cell Biology vol 61 no 1 pp 1ndash9 1993

[122] L P Jackson M Lewis H M Kent et al ldquoMolecular basis forrecognition of dilysine trafficking motifs by COPIrdquo Develop-mental Cell vol 23 pp 1ndash8 2012

[123] W Nickel K Sohn C Bunning and F T Wieland ldquop23 Amajor COPI-vesicle membrane protein constitutively cyclesthrough the early secretory pathwayrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 94 no21 pp 11393ndash11398 1997

[124] J C Semenza K G Hardwick N Dean and H R BPelham ldquoERD2 a yeast gene required for the receptor-mediatedretrieval of luminal ER proteins from the secretory pathwayrdquoCell vol 61 no 7 pp 1349ndash1357 1990

[125] I Majoul M Straub S W Hell R Duden and H D SolingldquoKDEL-cargo regulates interactions between proteins involvedin COPI vesicle traffic measurements in living cells usingFRETrdquo Developmental Cell vol 1 no 1 pp 139ndash153 2001

[126] B S Glick ldquoOrganization of the Golgi apparatusrdquo CurrentOpinion in Cell Biology vol 12 no 4 pp 450ndash456 2000

[127] R Blum D J Stephens and I Schulz ldquoLumenal targeted GFPused as a marker of soluble cargo visualises rapid ERGIC toGolgi traffic by a tubulo-vesicular networkrdquo Journal of CellScience vol 113 no 18 pp 3151ndash3159 2000

[128] J C Simpson T Nilsson and R Pepperkok ldquoBiogenesis oftubular ER-to-golgi transport intermediatesrdquoMolecular Biologyof the Cell vol 17 no 2 pp 723ndash737 2006

[129] K Hirschberg C M Miller J Ellenberg et al ldquoKinetic analysisof secretory protein traffic and characterization of Golgi toplasma membrane transport intermediates in living cellsrdquoJournal of Cell Biology vol 143 no 6 pp 1485ndash1503 1998

[130] D Toomre P Keller JWhite J C Olivo and K Simons ldquoDual-color visualization of trans-Golgi network to plasmamembranetraffic alongmicrotubules in living cellsrdquo Journal of Cell Sciencevol 112 no 1 pp 21ndash33 1999

[131] L Hermo A Rambourg and Y Clermont ldquoThree-dimensionalarchitecture of the cortical region of the Golgi apparatus in ratspermatidsrdquo American Journal of Anatomy vol 157 no 4 pp357ndash373 1980

[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

12 ISRN Cell Biology

[75] A Disanza and G Scita ldquoCytoskeletal regulation coordinatingactin and microtubule dynamics in membrane traffickingrdquoCurrent Biology vol 18 no 18 pp R873ndashR875 2008

[76] K G Campellone N J Webb E A Znameroski and M DWelch ldquoWHAMM is an Arp23 complex activator that bindsmicrotubules and functions in ER to golgi transportrdquo Cell vol134 no 1 pp 148ndash161 2008

[77] Q T Shen P P Hsiue C V Sindelar M D Welch KG Campellone and H W Wang ldquoStructural insights intoWHAMM-mediated cytoskeletal coordination during mem-brane remodelingrdquoThe Journal of Cell Biology vol 199 pp 111ndash124 2012

[78] T F Roth and K R Porter ldquoYolk protein uptake in the oocyteof the mosquito Aedes aegypti Lrdquo The Journal of Cell Biologyvol 20 pp 313ndash332 1964

[79] B M F Pearse ldquoClathrin a unique protein associated withintracellular transfer of membrane by coated vesiclesrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 73 no 4 pp 1255ndash1259 1976

[80] A Oprins R Duden T E Kreis H J Geuze and J W Slotldquo120573-COP localizes mainly to the cis-Golgi side in exocrinepancreasrdquo Journal of Cell Biology vol 121 no 1 pp 49ndash60 1993

[81] B M F Pearse and M S Robinson ldquoClathrin adaptors andsortingrdquo Annual Review of Cell Biology vol 6 pp 151ndash171 1990

[82] T Braulke and J S Bonifacino ldquoSorting of lysosomal proteinsrdquoBiochimica et BiophysicaActa vol 1793 no 4 pp 605ndash614 2009

[83] T Kirchhausen ldquoClathrinrdquo Annual Review of Biochemistry vol69 pp 699ndash727 2000

[84] E Rodriguez-Boulan and A Musch ldquoProtein sorting in theGolgi complex shifting paradigmsrdquo Biochimica et BiophysicaActa vol 1744 no 3 pp 455ndash464 2005

[85] M A McNiven H Cao K R Pitts and Y Yoon ldquoThe dynaminfamily of mechanoenzymes pinching in new placesrdquo Trends inBiochemical Sciences vol 25 no 3 pp 115ndash120 2000

[86] E Eisenberg and L E Greene ldquoMultiple roles of auxilin andHsc70 in clathrin-mediated endocytosisrdquo Traffic vol 8 no 6pp 640ndash646 2007

[87] C Barlowe L Orci T Yeung et al ldquoCOPII a membrane coatformed by sec proteins that drive vesicle budding from theendoplasmic reticulumrdquo Cell vol 77 no 6 pp 895ndash907 1994

[88] L C Bickford E Mossessova and J Goldberg ldquoA structuralview of the COPII vesicle coatrdquo Current Opinion in StructuralBiology vol 14 no 2 pp 147ndash153 2004

[89] D Jensen and R Schekman ldquoCOPII-mediated vesicle forma-tion at a glancerdquo Journal of Cell Science vol 124 no 1 pp 1ndash42011

[90] T Kirchhausen ldquoMaking COPII coatsrdquo Cell vol 129 no 7 pp1251ndash1252 2007

[91] C Barlowe ldquoCOPII and selective export from the endoplasmicreticulumrdquo Biochimica et Biophysica Acta vol 1404 no 1-2 pp67ndash76 1998

[92] J A Martınez-Menarguez H J Geuze J W Slot and JKlumperman ldquoVesicular tubular clusters between the ER andGolgi mediate concentration of soluble secretory proteins byexclusion fromCOPI-coated vesiclesrdquoCell vol 98 no 1 pp 81ndash90 1999

[93] K Saito M Chen F Bard et al ldquoTANGO1 facilitates cargoloading at endoplasmic reticulum exit sitesrdquo Cell vol 136 no5 pp 891ndash902 2009

[94] L Jin K B Pahuja K E Wickliffe et al ldquoUbiquitin-dependentregulation of COPII coat size and functionrdquo Nature vol 482pp 495ndash500 2012

[95] H P Hauri and A Schweizer ldquoThe endoplasmic reticulum-Golgi intermediate compartmentrdquo Current Opinion in CellBiology vol 4 no 4 pp 600ndash608 1992

[96] S I Bannykh T Rowe and W E Balch ldquoThe organizationof endoplasmic reticulum export complexesrdquo Journal of CellBiology vol 135 no 1 pp 19ndash35 1996

[97] J Saraste and E Kuismanen ldquoPre- and post-Golgi vacuolesoperate in the transport of Semliki Forest virus membraneglycoproteins to the cell surfacerdquo Cell vol 38 no 2 pp 535ndash549 1984

[98] A Schweizer J A M Fransen K Matter T E Kreis L GinselandH PHauri ldquoIdentification of an intermediate compartmentinvolved in protein transport from endoplasmic reticulum toGolgi apparatusrdquo European Journal of Cell Biology vol 53 no 2pp 185ndash196 1990

[99] H Ben-Takaya K Miura R Pepperkok and H P Hauri ldquoLiveimaging of bidirectional traffic from the ERGICrdquo Journal of CellScience vol 118 no 2 pp 357ndash367 2005

[100] Y C Zhang Y Zhou C Z Yang and D S Xiong ldquoA reviewof ERGIC-53 its structure functions regulation and relationswith diseasesrdquo Histology and Histopathology vol 24 no 9 pp1193ndash1204 2009

[101] J F Presley N B Cole T A Schroer K Hirschberg K JM Zaal and J Lippincott-Schwartz ldquoER-to-Golgi transportvisualized in living cellsrdquo Nature vol 389 no 6646 pp 81ndash851997

[102] J A Martınez-Menarguez H J Geuze and J Ballesta ldquoIdenti-fication of two types of beta-COP vesicles in the Golgi complexof rat spermatidsrdquo European Journal of Cell Biology vol 71 pp137ndash143 1996

[103] J Lippincott-Schwartz J G Donaldson A Schweizer et alldquoMicrotubule-dependent retrograde transport of proteins intothe ER in the presence of brefeldin A suggests an ER recyclingpathwayrdquo Cell vol 60 no 5 pp 821ndash836 1990

[104] A Girod B Storrie J C Simpson et al ldquoEvidence for a COP-I-independent transport route from the Golgi complex to theendoplasmic reticulumrdquo Nature Cell Biology vol 1 no 7 pp423ndash430 1999

[105] V Popoff F Adolf B Brugger and F Wieland ldquoCOPI buddingwithin the Golgi stackrdquo Cold Spring Harbor Perspectives inBiology vol 3 Article ID a005231 2011

[106] J Moelleken J Malsam M J Betts et al ldquoDifferential localiza-tion of coatomer complex isoforms within the Golgi apparatusrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 104 no 11 pp 4425ndash4430 2007

[107] L Orci B S Glick and J E Rothman ldquoA new type of coatedvesicular carrier that appears not to contain clathrin its possiblerole in protein transport within theGolgi stackrdquoCell vol 46 no2 pp 171ndash184 1986

[108] V Malhotra T Serafini L Orci J C Shepherd and J ERothman ldquoPurification of a novel class of coated vesiclesmediating biosynthetic protein transport through the Golgistackrdquo Cell vol 58 no 2 pp 329ndash336 1989

[109] M G Waters T Serafini and J E Rothman ldquolsquoCoatomerrsquo acytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesiclesrdquo Nature vol 349 no 6306 pp248ndash251 1991

[110] T Serafini L Orci M Amherdt M Brunner R A Kahn andJ E Rothman ldquoADP-ribosylation factor is a subunit of the coatof Golgi-derived COP-coated vesicles a novel role for a GTP-binding proteinrdquo Cell vol 67 no 2 pp 239ndash253 1991

ISRN Cell Biology 13

[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

[112] K Kawamoto Y Yoshida H Tamaki et al ldquoGBF1 a guaninenucleotide exchange factor for ADP-ribosylation factors islocalized to the cis-Golgi and involved inmembrane associationof the COPI coatrdquo Traffic vol 3 no 7 pp 483ndash495 2002

[113] R Garcıa-Mata T Szul C Alvarez and E Sztul ldquoADP-ribosylation factorCOPI-dependent events at the endoplas-mic reticulum-Golgi interface are regulated by the guaninenucleotide exchange factor GBF1rdquoMolecular Biology of the Cellvol 14 no 6 pp 2250ndash2261 2003

[114] H Inoue and P A Randazzo ldquoArf GAPs and their interactingproteinsrdquo Traffic vol 8 no 11 pp 1465ndash1475 2007

[115] G Tanigawa L Orci M Amherdt M Ravazzola J B Helmsand J E Rothman ldquoHydrolysis of bound GTP by ARF proteintriggers uncoating of Golgi- derived COP-coated vesiclesrdquoJournal of Cell Biology vol 123 no 6 pp 1365ndash1371 1993

[116] Y Shiba and P A Randazzo ldquoArfGAP1 function in COPImediated membrane traffic currently debated models andcomparison to other coat-binding ArfGAPsrdquo Histology andHistopathology vol 27 pp 1143ndash1153 2012

[117] J Bigay P Gounon S Roblneau and B Antonny ldquoLipidpacking sensed by ArfGAP1 couples COPI coat disassembly tomembrane bilayer curvaturerdquo Nature vol 426 no 6966 pp563ndash566 2003

[118] W Nickel J Malsam K Gorgas et al ldquoUptake by COPI-coatedvesicles of both anterograde and retrograde cargo is inhibitedby GTP120574S in vitrordquo Journal of Cell Science vol 111 no 20 pp3081ndash3090 1998

[119] R Beck M Rawet F T Wieland and D Cassel ldquoThe COPIsystemmolecularmechanisms and functionrdquo FEBS Letters vol583 pp 2701ndash2709 2009

[120] F Letourneur E C Gaynor S Hennecke et al ldquoCoatomeris essential for retrieval of dilysine-tagged proteins to theendoplasmic reticulumrdquo Cell vol 79 no 7 pp 1199ndash1207 1994

[121] R Schindler C Itin M Zerial F Lottspeich and H P HaurildquoERGIC-53 a membrane protein of the ER-Golgi intermediatecompartment carries an ER retention motifrdquo European Journalof Cell Biology vol 61 no 1 pp 1ndash9 1993

[122] L P Jackson M Lewis H M Kent et al ldquoMolecular basis forrecognition of dilysine trafficking motifs by COPIrdquo Develop-mental Cell vol 23 pp 1ndash8 2012

[123] W Nickel K Sohn C Bunning and F T Wieland ldquop23 Amajor COPI-vesicle membrane protein constitutively cyclesthrough the early secretory pathwayrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 94 no21 pp 11393ndash11398 1997

[124] J C Semenza K G Hardwick N Dean and H R BPelham ldquoERD2 a yeast gene required for the receptor-mediatedretrieval of luminal ER proteins from the secretory pathwayrdquoCell vol 61 no 7 pp 1349ndash1357 1990

[125] I Majoul M Straub S W Hell R Duden and H D SolingldquoKDEL-cargo regulates interactions between proteins involvedin COPI vesicle traffic measurements in living cells usingFRETrdquo Developmental Cell vol 1 no 1 pp 139ndash153 2001

[126] B S Glick ldquoOrganization of the Golgi apparatusrdquo CurrentOpinion in Cell Biology vol 12 no 4 pp 450ndash456 2000

[127] R Blum D J Stephens and I Schulz ldquoLumenal targeted GFPused as a marker of soluble cargo visualises rapid ERGIC toGolgi traffic by a tubulo-vesicular networkrdquo Journal of CellScience vol 113 no 18 pp 3151ndash3159 2000

[128] J C Simpson T Nilsson and R Pepperkok ldquoBiogenesis oftubular ER-to-golgi transport intermediatesrdquoMolecular Biologyof the Cell vol 17 no 2 pp 723ndash737 2006

[129] K Hirschberg C M Miller J Ellenberg et al ldquoKinetic analysisof secretory protein traffic and characterization of Golgi toplasma membrane transport intermediates in living cellsrdquoJournal of Cell Biology vol 143 no 6 pp 1485ndash1503 1998

[130] D Toomre P Keller JWhite J C Olivo and K Simons ldquoDual-color visualization of trans-Golgi network to plasmamembranetraffic alongmicrotubules in living cellsrdquo Journal of Cell Sciencevol 112 no 1 pp 21ndash33 1999

[131] L Hermo A Rambourg and Y Clermont ldquoThree-dimensionalarchitecture of the cortical region of the Golgi apparatus in ratspermatidsrdquo American Journal of Anatomy vol 157 no 4 pp357ndash373 1980

[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

ISRN Cell Biology 13

[111] C L Jackson and J E Casanova ldquoTurning on ARF the Sec7family of guanine-nucleotide-exchange factorsrdquo Trends in CellBiology vol 10 no 2 pp 60ndash67 2000

[112] K Kawamoto Y Yoshida H Tamaki et al ldquoGBF1 a guaninenucleotide exchange factor for ADP-ribosylation factors islocalized to the cis-Golgi and involved inmembrane associationof the COPI coatrdquo Traffic vol 3 no 7 pp 483ndash495 2002

[113] R Garcıa-Mata T Szul C Alvarez and E Sztul ldquoADP-ribosylation factorCOPI-dependent events at the endoplas-mic reticulum-Golgi interface are regulated by the guaninenucleotide exchange factor GBF1rdquoMolecular Biology of the Cellvol 14 no 6 pp 2250ndash2261 2003

[114] H Inoue and P A Randazzo ldquoArf GAPs and their interactingproteinsrdquo Traffic vol 8 no 11 pp 1465ndash1475 2007

[115] G Tanigawa L Orci M Amherdt M Ravazzola J B Helmsand J E Rothman ldquoHydrolysis of bound GTP by ARF proteintriggers uncoating of Golgi- derived COP-coated vesiclesrdquoJournal of Cell Biology vol 123 no 6 pp 1365ndash1371 1993

[116] Y Shiba and P A Randazzo ldquoArfGAP1 function in COPImediated membrane traffic currently debated models andcomparison to other coat-binding ArfGAPsrdquo Histology andHistopathology vol 27 pp 1143ndash1153 2012

[117] J Bigay P Gounon S Roblneau and B Antonny ldquoLipidpacking sensed by ArfGAP1 couples COPI coat disassembly tomembrane bilayer curvaturerdquo Nature vol 426 no 6966 pp563ndash566 2003

[118] W Nickel J Malsam K Gorgas et al ldquoUptake by COPI-coatedvesicles of both anterograde and retrograde cargo is inhibitedby GTP120574S in vitrordquo Journal of Cell Science vol 111 no 20 pp3081ndash3090 1998

[119] R Beck M Rawet F T Wieland and D Cassel ldquoThe COPIsystemmolecularmechanisms and functionrdquo FEBS Letters vol583 pp 2701ndash2709 2009

[120] F Letourneur E C Gaynor S Hennecke et al ldquoCoatomeris essential for retrieval of dilysine-tagged proteins to theendoplasmic reticulumrdquo Cell vol 79 no 7 pp 1199ndash1207 1994

[121] R Schindler C Itin M Zerial F Lottspeich and H P HaurildquoERGIC-53 a membrane protein of the ER-Golgi intermediatecompartment carries an ER retention motifrdquo European Journalof Cell Biology vol 61 no 1 pp 1ndash9 1993

[122] L P Jackson M Lewis H M Kent et al ldquoMolecular basis forrecognition of dilysine trafficking motifs by COPIrdquo Develop-mental Cell vol 23 pp 1ndash8 2012

[123] W Nickel K Sohn C Bunning and F T Wieland ldquop23 Amajor COPI-vesicle membrane protein constitutively cyclesthrough the early secretory pathwayrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 94 no21 pp 11393ndash11398 1997

[124] J C Semenza K G Hardwick N Dean and H R BPelham ldquoERD2 a yeast gene required for the receptor-mediatedretrieval of luminal ER proteins from the secretory pathwayrdquoCell vol 61 no 7 pp 1349ndash1357 1990

[125] I Majoul M Straub S W Hell R Duden and H D SolingldquoKDEL-cargo regulates interactions between proteins involvedin COPI vesicle traffic measurements in living cells usingFRETrdquo Developmental Cell vol 1 no 1 pp 139ndash153 2001

[126] B S Glick ldquoOrganization of the Golgi apparatusrdquo CurrentOpinion in Cell Biology vol 12 no 4 pp 450ndash456 2000

[127] R Blum D J Stephens and I Schulz ldquoLumenal targeted GFPused as a marker of soluble cargo visualises rapid ERGIC toGolgi traffic by a tubulo-vesicular networkrdquo Journal of CellScience vol 113 no 18 pp 3151ndash3159 2000

[128] J C Simpson T Nilsson and R Pepperkok ldquoBiogenesis oftubular ER-to-golgi transport intermediatesrdquoMolecular Biologyof the Cell vol 17 no 2 pp 723ndash737 2006

[129] K Hirschberg C M Miller J Ellenberg et al ldquoKinetic analysisof secretory protein traffic and characterization of Golgi toplasma membrane transport intermediates in living cellsrdquoJournal of Cell Biology vol 143 no 6 pp 1485ndash1503 1998

[130] D Toomre P Keller JWhite J C Olivo and K Simons ldquoDual-color visualization of trans-Golgi network to plasmamembranetraffic alongmicrotubules in living cellsrdquo Journal of Cell Sciencevol 112 no 1 pp 21ndash33 1999

[131] L Hermo A Rambourg and Y Clermont ldquoThree-dimensionalarchitecture of the cortical region of the Golgi apparatus in ratspermatidsrdquo American Journal of Anatomy vol 157 no 4 pp357ndash373 1980

[132] M S Cooper A H Cornell-Bell A Chernjavsky J W Daniand S J Smith ldquoTubulovesicular processes emerge from trans-Golgi cisternae extend along microtubules and interlink adja-cent trans-Golgi elements into a reticulumrdquo Cell vol 61 no 1pp 135ndash145 1990

[133] N B Cole C L Smith N Sciaky M Terasaki M Edidin and JLippincott-Schwartz ldquoDiffusional mobility of Golgi proteins inmembranes of living cellsrdquo Science vol 273 no 5276 pp 797ndash801 1996

[134] S J Scales R Pepperkok and T E Kreis ldquoVisualization of ER-to-Golgi transport in living cells reveals a sequential mode ofaction for COPII and COPIrdquo Cell vol 90 no 6 pp 1137ndash11481997

[135] M S Ladinsky J R Kremer P S Furcinitti J R McIntosh andK E Howell ldquoHVEM tomography of the trans-Golgi networkstructural insights and identification of a lace-like vesicle coatrdquoJournal of Cell Biology vol 127 no 1 pp 29ndash38 1994

[136] A Trucco R S Polischuck O Martella et al ldquoSecretory traffictriggers the formation of tubular continuities across Golgi sub-compartmentsrdquoNature Cell Biology vol 6 no 11 pp 1071ndash10812004

[137] B J Marsh N Volkmann J R McIntosh and K E HowellldquoDirect continuities between cisternae at different levels of theGolgi complex in glucose-stimulated mouse islet beta cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 15 pp 5565ndash5570 2004

[138] E Martınez-Alonso G Egea J Ballesta and J A Martınez-Menarguez ldquoStructure and dynamics of the Golgi complex at15 degrees C low temperature induces the formation of Golgi-derived tubulesrdquo Traffic vol 6 pp 32ndash44 2005

[139] E Martınez-Alonso J Ballesta and J A Martınez-MenarguezldquoLow-temperature-induced Golgi tubules are transient mem-branes enriched in molecules regulating intra-Golgi transportrdquoTraffic vol 8 no 4 pp 359ndash368 2007

[140] T E Kreis ldquoRegulation of vesicular and tubular membranetraffic of the Golgi complex by coat proteinsrdquo Current Opinionin Cell Biology vol 4 no 4 pp 609ndash615 1992

[141] M Lowe and T E Kreis ldquoRegulation of membrane traffic inanimal cells by COPIrdquo Biochimica et Biophysica Acta vol 1404no 1-2 pp 53ndash66 1998

[142] M Krauss J Y Jia A Roux et al ldquoArf1-GTP-induced tubuleformation suggests a function of arf family proteins in curvatureacquisition at sites of vesicle buddingrdquo Journal of BiologicalChemistry vol 283 no 41 pp 27717ndash27723 2008

[143] A Roux G Cappello J Cartaud J Prost B Goud andP Bassereau ldquoA minimal system allowing tubulation with

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

14 ISRN Cell Biology

molecular motors pulling on giant liposomesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 8 pp 5394ndash5399 2002

[144] P de Figueiredo D Drecktrah R S Polizotto N B ColeJ Lippincott-Schwartz and W J Brown ldquoPhospholipase A

2

antagonists inhibit constitutive retrograde membrane traffic tothe reticulumrdquo Traffic vol 1 no 6 pp 504ndash511 2000

[145] W J Brown K Chambers and A Doody ldquoPhospholipase A2(PLA2) enzymes in membrane trafficking mediators of mem-brane shape and functionrdquo Traffic vol 4 no 4 pp 214ndash2212003

[146] E San Pietro M Capestrano E V Polishchuk et al ldquoGroupIV phospholipase A2120572 controls the formation of inter-cisternalcontinuities involved in intra-golgi transportrdquo PLoS Biologyvol 7 no 9 Article ID e1000194 2009

[147] J A Schmidt D N Kalkofen KW Donovan andW J BrownldquoA role for phospholipase A

2

activity in membrane tubuleformation and TGN traffickingrdquo Traffic vol 11 no 12 pp 1530ndash1536 2010

[148] C L Baron and V Malhotra ldquoRole of diacylglycerol in PKDrecruitment to the TGN and protein transport to the plasmamembranerdquo Science vol 295 no 5553 pp 325ndash328 2002

[149] I Fernandez-Ulibarri M Vilella F Lazaro-Dieguez et alldquoDiacylglycerol is required for the formation of COPI vesiclesin the Golgi-to-ER transport pathwayrdquoMolecular Biology of theCell vol 18 no 9 pp 3250ndash3263 2007

[150] J S Yang H Gad S Y Lee et al ldquoA role for phosphatidic acidin COPI vesicle fission yields insights into Golgi maintenancerdquoNature Cell Biology vol 10 no 10 pp 1146ndash1153 2008

[151] J S Yang C Valente R S Polishchuk et al ldquoCOPI acts in bothvesicular and tubular transportrdquoNature Cell Biology vol 13 no8 pp 996ndash1003 2011

[152] M Tomas E Martınez-Alonso J Ballesta and J A Martınez-Menarguez ldquoRegulation of ER-Golgi intermediate compart-ment tubulation and mobility by COPI coats motor proteinsand microtubulesrdquo Traffic vol 11 pp 616ndash625 2010

[153] H Ben-Tekaya R A Kahn and H P Hauri ldquoADP ribosylationfactors 1 and 4 and group VIA phospholipase A2 regulate mor-phology and intraorganellar traffic in the endoplasmic retic-ulum-golgi intermediate compartmentrdquo Molecular Biology ofthe Cell vol 21 no 23 pp 4130ndash4140 2010

[154] E V Polishchuk A Di Pentima A Luini and R S PolishchukldquoMechanism of constitutive export from the golgi bulk flow viathe formation protrusion and en bloc cleavage of large trans-golgi network tubular domainsrdquo Molecular Biology of the Cellvol 14 no 11 pp 4470ndash4485 2003

[155] A A Mironov A A Mironov Jr G V Beznoussenko et alldquoER-to-Golgi carriers arise through direct en bloc protrusionandmultistagematuration of specialized ER exit domainsrdquoDevCell vol 5 pp 583ndash594 2003

[156] H Horstmann C P Ng B L Tang and W Hong ldquoUltra-structural characterization of endoplasmic reticulummdashGolgitransport containers (EGTC)rdquo Journal of Cell Science vol 115no 22 pp 4263ndash4273 2002

[157] J S Bonifacino and B S Glick ldquoThe mechanisms of vesiclebudding and fusionrdquo Cell vol 116 no 2 pp 153ndash166 2004

[158] W Hong ldquoSNAREs and trafficrdquo Biochimica et Biophysica Actavol 1744 no 3 pp 493ndash517 2005

[159] R Jahn and R H Scheller ldquoSNAREsmdashengines for membranefusionrdquo Nature Reviews Molecular Cell Biology vol 7 no 9 pp631ndash643 2006

[160] J Malsam and T H Sollner ldquoOrganization of SNAREs withinthe Golgi stackrdquo Cold Spring Harbor Perspectives in Biology vol3 Article ID a005249 2011

[161] A Volchuk M Ravazzola A Perrelet et al ldquoCountercurrentdistribution of two distinct SNARE complexes mediating trans-port within the Golgi stackrdquo Molecular Biology of the Cell vol15 no 4 pp 1506ndash1518 2004

[162] O Laufman A KedanW Hong and S Lev ldquoDirect interactionbetween the COG complex and the SM protein Sly1 is requiredforGolgi SNAREpairingrdquoTheEMBO Journal vol 28 no 14 pp2006ndash2017 2009

[163] H Stenmark ldquoRab GTPases as coordinators of vesicle trafficrdquoNature Reviews Molecular Cell Biology vol 10 no 8 pp 513ndash525 2009

[164] M Zerial and H McBride ldquoRab proteins as membrane orga-nizersrdquo Nature Reviews Molecular Cell Biology vol 2 no 2 pp107ndash117 2001

[165] S Liu and B Storrie ldquoAre Rab proteins the link between Golgiorganization and membrane traffickingrdquo Cell vol 69 no 24pp 4093ndash4106 2012

[166] M Tomas M P Marın E Martınez-Alonso et al ldquoAlcoholinduces Golgi fragmentation in differentiated PC12 cells byderegulating Rab1-dependent ER-to-Golgi transportrdquo Histo-chemistry and Cell Biology vol 138 pp 489ndash501 2012

[167] W O Rendon E Martınez-Alonso M Tomas N Martınez-Martınez and J A Martınez-Menarguez ldquoGolgi fragmentationis Rab and SNARE dependent in cellular models of Parkinsonrsquosdiseaserdquo Histochemistry and Cell Biology 2012

[168] OMartinez A Schmidt J Salamero B HoflackM Roa and BGoud ldquoThe small GTP-binding protein rab6 functions in intra-Golgi transportrdquo Journal of Cell Biology vol 127 no 6 I pp1575ndash1588 1994

[169] JWhite L Johannes FMallard et al ldquoRab6 coordinates a novelGolgi to ER retrograde transport pathway in live cellsrdquo Journalof Cell Biology vol 147 no 4 pp 743ndash759 1999

[170] I Grigoriev D Splinter N Keijzer et al ldquoRab6 regulatestransport and targeting of exocytotic carriersrdquo DevelopmentalCell vol 13 no 2 pp 305ndash314 2007

[171] S Miserey-Lenkei G Chalancon S Bardin E Formstecher BGoud and A Echard ldquoRab and actomyosin-dependent fissionof transport vesicles at the golgi complexrdquo Nature Cell Biologyvol 12 no 7 pp 645ndash654 2010

[172] I Grigoriev K L Yu E Martinez-Sanchez et al ldquoRab6 Rab8and MICAL3 cooperate in controlling docking and fusion ofexocytotic carriersrdquo Current Biology vol 2 pp 967ndash974 2011

[173] B Storrie M Micaroni G P Morgan et al ldquoElectron tomog-raphy reveals that Rab6 is essential to the trafficking of trans-Golgi clathrin and COPI-coated vesicles and the maintenanceof Golgi cisternal numberrdquo Traffic vol 13 pp 727ndash744 2012

[174] J Y Zheng T Koda T Fujiwara M Kishi Y Ikehara andM Kakinuma ldquoA novel Rab GTPase Rab33B is ubiquitouslyexpressed and localized to the medial Golgi cisternaerdquo Journalof Cell Science vol 111 no 8 pp 1061ndash1069 1998

[175] T Starr Y SunNWilkins andB Storrie ldquoRab33b andRab6 arefunctionally overlapping regulators of Golgi homeostasis andtraffickingrdquo Traffic vol 11 no 5 pp 626ndash636 2010

[176] G V Pusapati G Luchetti and S R Pfeffer ldquoRic1Rgp1 com-plex a guanine nucleotide exchange factor for the late GolgiRab6A GTPase and an effector of the medial Golgi Rab33BGTPaserdquo The Journal of Biological Chemistry vol 287 no 50pp 42129ndash42137 2012

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

ISRN Cell Biology 15

[177] E Sztul and V Lupashin ldquoRole of vesicle tethering factors in theER-Golgi membrane trafficrdquo FEBS Letters vol 583 no 23 pp3770ndash3783 2009

[178] I Barinaga-Rementeria Ramirez and M Lowe ldquoGolgins andGRASPs holding the Golgi togetherrdquo Seminars in Cell andDevelopmental Biology vol 20 no 7 pp 770ndash779 2009

[179] M A DeMatteis A AMironov and G V Beznoussenko ldquoTheGolgi ribbon and the function of the golginsrdquo in The GolgiAp-paratus A A Mironov and M Pavelka Eds pp 223ndash246Springer NewYork NY USA 2008

[180] V J Miller and D Ungar ldquoRersquoCOGrsquonition at the Golgirdquo Trafficvol 13 pp 891ndash897 2012

[181] M Sacher Y G Kim A Lavie B H Oh and N Segev ldquoTheTRAPP complex insights into its architecture and functionrdquoTraffic vol 9 no 12 pp 2032ndash2042 2008

[182] J E Rothman and F T Wieland ldquoProtein sorting by transportvesiclesrdquo Science vol 272 no 5259 pp 227ndash234 1996

[183] J E Rothman and L Orci ldquoMolecular dissection of the secre-tory pathwayrdquo Nature vol 355 no 6359 pp 409ndash415 1992

[184] P Chardin and F McCormick ldquoBrefeldin A the advantage ofbeing uncompetitiverdquo Cell vol 97 no 2 pp 153ndash155 1999

[185] P Cosson and F Letourneur ldquoCoatomer interaction with Di-lysine endoplasmic reticulum retention motifsrdquo Science vol263 no 5153 pp 1629ndash1632 1994

[186] L Orci M Ravazzola A Volchuk et al ldquoAnterograde flow ofcargo across the Golgi stack potentially mediated via bidirec-tional ldquopercolatingrdquo COPI vesiclesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no19 pp 10400ndash10405 2000

[187] L Orci M Stamnes M Ravazzola et al ldquoBidirectional trans-port by distinct populations of COPI-coated vesiclesrdquo Cell vol90 no 2 pp 335ndash349 1997

[188] J A Martınez-Menarguez R Prekeris V M J Oorschot etal ldquoPeri-Golgi vesicles contain retrograde but not anterogradeproteins consistent with the cisternal progression model ofintra-Golgi transportrdquo Journal of Cell Biology vol 155 no 7 pp1213ndash1224 2001

[189] P Cosson M Amherdt J E Rothman and L Orci ldquoA residentGolgi protein is excluded fromperi-Golgi vesicles inNRK cellsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12831ndash12834 2002

[190] L Bonfanti A A Mironov J A Martınez-Menarguez et alldquoProcollagen traverses the Golgi stack without leaving thelumen of cisternae evidence for cisternal maturationrdquo Cell vol95 no 7 pp 993ndash1003 1998

[191] M Melkonian B Becker and D Becker ldquoScale formation inalgaerdquo Journal of Electron Microscopy Technique vol 17 no 2pp 165ndash178 1991

[192] A Volchuk M Amherdt M Ravazzola et al ldquoMegavesiclesimplicated in the rapid transport of intracisternal aggregatesacross the Golgi stackrdquo Cell vol 102 no 3 pp 335ndash348 2000

[193] P P Grasse ldquoUltrastructure polarity and reproduction of Golgiapparatusrdquo Comptes Rendus Hebdomadaires des Seances delrsquoAcademie des Sciences vol 245 no 16 pp 1278ndash1281 1957

[194] B S Glick and V Malhotra ldquoThe curious status of the Golgiapparatusrdquo Cell vol 95 no 7 pp 883ndash889 1998

[195] B S Glick T Elston and G Oster ldquoA cisternal maturationmechanismcan explain the asymmetry of theGolgi stackrdquoFEBSLetters vol 414 no 2 pp 177ndash181 1997

[196] E Losev C A Reinke J Jellen D E Strongin B J Bevis andB S Glick ldquoGolgi maturation visualized in living yeastrdquoNaturevol 441 no 7096 pp 1002ndash1006 2006

[197] KMatsuura-Tokita M Takeuchi A Ichihara KMikuriya andA Nakano ldquoLive imaging of yeast Golgi cisternal maturationrdquoNature vol 441 no 7096 pp 1007ndash1010 2006

[198] H R B Pelham and J E Rothman ldquoThe debate about transportin the golgimdashtwo sides of the same coinrdquo Cell vol 102 no 6pp 713ndash719 2000

[199] G H Patterson K Hirschberg R S Polishchuk D GerlichR D Phair and J Lippincott-Schwartz ldquoTransport throughthe Golgi apparatus by rapid partitioning within a two-phasemembrane Systemrdquo Cell vol 133 no 6 pp 1055ndash1067 2008

[200] A A Mironov and G V Beznoussenko ldquoThe kiss-and-runmodel of intra-Golgi transportrdquo International Journal of Molec-ular Sciences vol 13 pp 6800ndash6819 2012

[201] G Griffiths ldquoGut thoughts on the golgi complexrdquo Traffic vol 1no 9 pp 738ndash745 2000

[202] C Golgi ldquoSur la structure des cellules nerveusesrdquo ArchivesItaliennes de Biologie vol 30 pp 60ndash71 1898

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology