Review Article Roles of Rack1 Proteins in Fungal Pathogenesis

Review ArticleRoles of Rack1 Proteins in Fungal Pathogenesis

Xue Zhang1 Rashmi Jain234 and Guotian Li234

1Department of Botany and Plant Pathology Purdue University West Lafayette IN 47907 USA2Department of Plant Pathology and the Genome Center University of California Davis CA 95616 USA3Feedstocks Division Joint BioEnergy Institute Lawrence Berkeley National Laboratory Berkeley CA 94720 USA4Biological Systems and Engineering Division Lawrence Berkeley National Laboratory 1 Cyclotron RoadBerkeley CA 94720 USA

Correspondence should be addressed to Guotian Li gtliucdavisedu

Received 22 May 2016 Accepted 16 August 2016

Academic Editor Gyorgy Schneider

Copyright copy 2016 Xue Zhang et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Pathogenic fungi cause diseases on various organisms Despite their differences in life cycles fungal pathogens use well-conservedproteins and pathways to regulate developmental and infection processes In this review we focus on Rack1 a multifacetedscaffolding protein involved in various biological processes Rack1 is well conserved in eukaryotes and plays important roles infungi though limited studies have been conducted To accelerate the study of Rack1 proteins in fungi we review the functionsof Rack1 proteins in model and pathogenic fungi and summarize recent progress on how Rack1 proteins are involved in fungalpathogenesis

1 Introduction

Diseases caused by pathogenic fungi pose a serious threat tohuman animal plant and ecosystem health [1 2] Particu-larly plant diseases caused by fungi for example rice blastand wheat rust have long been known as widespread threatsto global food security [1 3] In pathogenic fungi key proteinsand signal transduction pathways play conserved roles in theregulation of different developmental and infection processesand are therefore valuable targets for controlling these devas-tating diseases [4 5]

Heterotrimeric G proteins are involved in environmentalsensing of nutrients pheromones stresses and other stimuliin eukaryotes [6] The heterotrimeric G protein complexconsists of G120572 G120573 and G120574 subunits In the signal trans-duction pathway heterotrimeric G proteins are activated byG protein-coupled receptors (GPCRs) that perceive varioussignals In the absence of a stimulus the GDP-bound G120572monomer and the G120573120574 dimer form an inactive complexwith the GPCR Binding of the ligand to the GPCR triggersexchange of GDP with GTP in association with G120572 and sub-sequent dissociation of G120572 fromG120573120574 and the released activeform of the G120573120574 dimer interacts with other effector proteins

to activate downstream signal transduction pathways Oneof them is the cyclic adenosine 3101584051015840-monophosphateproteinkinase A (cAMPPKA) pathway The GPCR activates theadenylyl cyclase which catalyzes the formation of cAMP thatin turn activates the PKA-mediated signaling cascades cAMPis degraded by the cyclic nucleotide phosphodiesterasewhich together with the adenylyl cyclase balances the levelof cAMP in the cell [7] Another pathway activated bythe GPCR is the mitogen-activated protein kinase (MAPK)pathway consisting of three sequentially activating kinaseswith the upstream MAPK kinase kinases (MAPKKKs) per-ceiving signals from the receptors and activating MAPKkinases (MAPKKs) that in turn activate the MAPKs throughphosphorylation for example Fus3Kss1 and Slt2 in Saccha-romyces cerevisiae [8] The phosphorylated MAPKs activaterelated transcription factors which in turn regulate genes indifferent biological processes

Receptor for activated C kinase 1 (RACK1) was orig-inally identified as the binding protein for activated pro-tein kinase C [9 10] Rack1 belongs to the WD-repeat-containing proteins and contains sevenWD40 repeatsTheseseven WD40 repeats assemble into a typical seven-bladed120573-propeller structure that provides an interactive platform

Hindawi Publishing CorporationBioMed Research InternationalVolume 2016 Article ID 4130376 8 pageshttpdxdoiorg10115520164130376

2 BioMed Research International

for the binding of other proteins [11] Rack1 proteins areconstitutively expressed in eukaryotes Rack1 has been inten-sively studied in mammalian cells [12 13] Rack1 functionsin angiogenesis tumor growth cell migration apoptosisautophagy neuronal response proper function of the circa-dian clock defense responses against virus infection chro-matin remodeling transcriptional and translational regula-tions and cAMPPKA and MAPK pathways [11ndash15] Rack1regulates these biological processes through the control ofprotein complex assembly [13] In plants Rack1 proteins arefunctional in seed germination leaf production floweringhormonal signaling and bioticabiotic stress responses [16ndash18] The emerging role of Rack1 as a scaffold protein in theMAPK pathway in Arabidopsis thaliana has been recentlypublished [19ndash21] In protozoan parasites Rack1 proteins arecritical for effective mammalian parasitization by Leishmaniamajor and Trypanosoma brucei which cause leishmaniasisand African trypanosomiasis respectively [22ndash24] The Lmajor LACK (Leishmania homologue of mammalian RACK)antigen is also a target of the immune response in mice andtherefore a vaccine candidate for human leishmaniasis [22]In Plasmodium falciparum the most lethal malarial parasitethe Rack1 protein inhibits Ca2+ signaling of the mammaliancells and subverts the host intracellular environment animportantmechanism for parasite survival [25] In summaryRack1 proteins play important roles across a wide variety oforganisms In this review we summarize recent progress onRack1 proteins in model and pathogenic fungi

2 Rack1 Homologs Are Well Conserved

The Rack1 protein is found in many organisms including thealga Chlamydomonas reinhardtii yeasts filamentous fungiplants nematodes insects and vertebrates indicating that itis evolutionarily conserved [16 58] In fungi Rack1 proteinsare well conserved in most species of ChytridiomycotaZygomycota Glomeromycota Ascomycota and Basidiomy-cota (Figure 1) Rack1 proteins are also well conserved infungi-like microbes oomycetes which cause serious plantdiseases such as potato late blight and sudden oak death[59 60]

Rack1 proteins are functionally conserved Multiple com-plementation assays show that Rack1 proteins are func-tionally interchangeable among different species or evenacross kingdoms [26 49 52] For example the mammalianRACK1 gene can rescue the defects of rack1 mutants inSchizosaccharomyces pombe andAspergillus nidulans [40 52]The Neurospora crassa cpc-2 and the rat RACK1 genes areable to complement the cpc2mutant in S pombe [26] RACK1genes of A nidulans and yeasts (S cerevisiae S pombeand Candida albicans) can largely rescue the hyphal growthdefects of the cpcB deletion mutant in Aspergillus fumigatus[49] Species-specific roles of Rack1 proteins have also beenshown in different fungi For example the A nidulans CpcBortholog but not theRACK1 genes from yeasts can completelyrescue the conidiation defect of theA fumigatus cpcBmutant[49] Taken together these studies show the well conservedand unique roles of Rack1 proteins in different fungal species

3 Rack1 Proteins in Model Fungi

31 Saccharomyces cerevisiae In S cerevisiae a modelunicellular eukaryote the Rack1 homolog known as Asc1is involved in multiple biological processes (Table 1) Asc1is involved in the general amino acid control (GAAC) thatprovides the cell with sufficient amounts of protein precursorsunder conditions of amino acid limitation [61] Amino acidstarvation in yeast promotes translation of GCN4 whichthen causes expression of genes required for synthesis ofall 20 amino acids This response is called GAAC In theabsence of amino acid starvation Asc1 represses Gcn4 [26]a transcription activator of the GAAC pathway [61] InS pombe studies suggest that Cpc2 promotes the GAACresponse under the amino acid starvation condition [41]

Asc1 functions as the G120573 subunit for Gpa2 and inter-acts directly with the G120572 subunit as a guanine nucleotidedissociation inhibitor that inhibits the guanine nucleotideexchange activity of G120572 Asc1 negatively regulates glucose-mediated signaling via two pathways In the cAMPPKApathway Asc1 binds to the effector enzyme adenylyl cyclase(Cyr1) in addition to Gpa2 and represses the production ofcAMP in response to glucose stimulation [27] Secondly Asc1is involved in the Kss1MAPK pathway by binding to Ste20 Inthe asc1 mutant basal phosphorylation of Kss1 is enhancedSimilarly under pheromone stimulus the asc1mutant showsenhanced phosphorylation of both Fus3 and Kss1 but showsreduced expression of gene FLO11 key components forpheromone responsemating andfilamentous growth [8 28]

Asc1 is involved in cell wall integrity and stress responses[28ndash31] The asc1 mutant is hypersensitive to cell wall dam-aging agents iron chelators and nitrosative stress [29 31]Similarly Cpc2 is involved in stress responses in S pombe[42] The cell wall integrity defect of the asc1 mutant mostlikely results from PKC-independent mechanisms becausethe double-knockout mutant (asc1 pkc1) shows synergisticsensitivity to cell wall stresses [29] Interestingly the basalphosphorylation level of the MAPK Slt2 is higher in theasc1 mutant [32] indicating that Asc1 regulates the SLT2MAPKpathway In addition Asc1 regulates replication stress-induced formation of P-bodies that consist of many enzymesinvolved in mRNA turnover [33 62] Asc1 also regulates cellsize Compared to the wild-type control the cell size of theasc1 mutant is larger in S cerevisiae [28] The enlarged cellsize is also observed in the cpc2mutant in S pombe [43]

Asc1 executes its many functions by interacting withdifferent proteins and regulating the transcription and trans-lation of different genes De novo proteome analysis indi-cates that the asc1 mutant shows 50 elevated de novobiosynthesis of soluble proteins compared to the wild typeIn contrast expression of insoluble proteins is reduced bynearly a quarter in the asc1 mutant [31] The protein levelof several transcription factors including Rap1 Tec1 Phd1and Flo8 is downregulated but the protein level of Ste12 isupregulated over 6-fold in the asc1mutant [31] Interestinglyall three transcription factors Flo8 Ste12 and Tec1 positivelyregulate the expression of gene FLO11 Flo8 and Tec1 aredownregulated and Ste12 is upregulated in the asc1 mutantHowever the expression of gene FLO11 is still downregulated

BioMed Research International 3

Glomeromycetes Chytridiomycetes

Ascomycetes Zygomycetes

AnimalsPlants

TTric

hoto

my

Oomycetes

Basidiomycetes

Protozoa

1000

1000

325

501

990

512

359

1000

904

929

856

655

868

820

1000

493

1000

975

1000

689

998

1000

601

995

980

1000

357

977383

932949

713 555

894 496

1000

802

353

504

466

379

977

989

Ago

Sce

Ssc

Bci

Sma

Ncr

BbaMro

Cor

FgrFveG

gr

Fox

Cal

Spo

HsaMmu

Dme

CelAthOsaCrePraPi

nPsoH

arLma

BdeRir

Mci

Cci

Sco

Mla

Pgr

Cne

Uma

Afu

Acl

Afl

Aor

Ang

Ani

Hca

Mgr

Mor

Tbr

Figure 1 Phylogenetic tree of Rack1 proteins of eukaryotes The predicted amino acid sequences of Rack1 proteins were alignedwith ClustalX multiple sequence alignment program and the phylogenetic tree was visualized using FigTree program Numbersindicate the 1000-bootstrap value of each branch The accession number of each Rack1 protein is indicated in parentheses AclAspergillus clavatus (XP 0012721691) Afl Aspergillus flavus (EED471441) Afu Aspergillus fumigatus (EDP50669) Ago Ashbya gossypii(NP 9857461) AngAspergillus niger (XP 0013893071) AniAspergillus nidulans (XP 661767) AorAspergillus oryzae (XP 0018167481) AthArabidopsis thaliana (NP 1732481) Bba Beauveria bassiana (XP 0086002661) Bci Botrytis cinerea (XP 0015513141) Bde Batrachochytriumdendrobatidis (XP 0066790851) Cal Candida albicans (P837742) Cci Coprinus cinereus (XP 0018304411) Cel Caenorhabditis elegans(NP 5018591) Cne Cryptococcus neoformans (AAX945641) Cor Colletotrichum orbiculare (ENH837071) Cre Chlamydomonas reinhardtii(XP 0016980651) Dme Drosophila melanogaster (NP 4772691) Fgr Fusarium graminearum (XP 0113187721) Fox Fusarium oxysporum(KNB029161) Fve Fusarium verticillioides (EWG399801) Ggr Gaeumannomyces graminis (XP 0092258661) Har Hyaloperonosporaarabidopsidis (HpaP813344) Hca Histoplasma capsulatum (EGC414011) Hsa Homo sapiens (NP 0060891) Lma Leishmania major(XP 0016845601) Mci Mucor circinelloides (OAD008381) Mgr Mycosphaerella graminicola (XP 0038528991) Mla Melampsora laricis-populina (EGG076651) Mmu Mus musculus (NP 0321691) Mor Magnaporthe oryzae (XP 0037108161) Mro Metarhizium robertsii(XP 0078244281) Ncr Neurospora crassa (CAA574601) Osa Oryza sativa (NP 0010439101) Pgr Puccinia graminis (EFP891292) PinPhytophthora infestans (XP 0029031891) Pra Phytophthora ramorum (PSURA 41642) Pso Phytophthora sojae (XP 0095310421) RirRhizophagus irregularis (ESA038661) Sce Saccharomyces cerevisiae (NP 0138341) Sco Schizophyllum commune (XP 0030298821) SmaSordaria macrospora (XP 0033514401) Spo Schizosaccharomyces pombe (AAA568652) Ssc Sclerotinia sclerotiorum (EDN914971) TbrTrypanosoma brucei (XP 8292011) Uma Ustilago maydis (XP 0113888291)


Table 1 Rack1 proteins in model and pathogenic fungi

Species Rack1 Functions ReferencesAscomycetes

Saccharomyces cerevisiae Asc1

General amino acid control pheromone responsemating and filamentous growth pseudohyphaldevelopment translation regulation and fidelitycell size cell wall integrity stress responses and

cAMPPKA and MAPK pathways

[8 26ndash39]

Schizosaccharomyces pombe Cpc2Stress responses cell wall integrity cell size

mitotic commitment positive role in the generalamino acid control response cell cycleprogression and meiotic development

[40ndash43]

Candida albicanslowast Asc1 Growth filamentation adhesive growth invasionand virulence [44 45]

Neurospora crassa cpc-2 Cross-pathway control sexual reproduction andthe heterotrimeric G protein complex [46ndash48]

Aspergillus fumigatuslowast CpcBGrowth conidiation conidial germination cellwall integrity mycotoxin (gliotoxin) production

virulence and antifungal drug resistance[49ndash51]

Aspergillus nidulans CpcBGrowth conidiation conidial germination sexual

development mycotoxin (sterigmatocystin)production and cross-pathway control

[50 52]

Basidiomycetes

Cryptococcus neoformanslowast Gib2 Growth virulence a scaffolding adaptor proteinand a G120573-like subunit of the cAMPPKA pathway [53ndash56]

Ustilago maydissect Rak1Growth cell wall integrity cell fusion filamentformation appressorium formation virulence

and a ribosomal protein[53 57]

lowastHuman pathogenssectPlant pathogens

in the asc1 mutant and the invasive growth is impaired [28]Some proteins involved in cell wall biogenesis and overallcell morphology were found to be significantly reduced inthe asc1 mutant Almost 50 of all proteins found to beregulated in asc1 cells are involved in energy metabolismThis comprehensive group is composed of proteins takingpart in glycolysis mitochondrial biogenesis and respirationoxidative stress and fermentation The findings of de novoproteome analysis are consistent with the phenotypes of theasc1mutant [31]

Asc1 is involved in translational regulation in S cerevisiaeThe Asc1 protein is a core component of the small (40S)ribosomal subunit [34ndash36] Phosphoproteome and Westernblotting studies show that the ribosomal protein Asc1 affectsthe phosphorylation of the eukaryotic translation initiationfactors eIF2120572 and eIF4A and the ribosome-associated com-plex RAC [28] Asc1 also participates in nascent peptide-dependent translation arrest at consecutive basic amino acidsequences and the 40S subunit binding to Rack1 is crucialfor translation arrest Translation arrest of an mRNA by anascent peptide leads to cleavage of the mRNA as well as tocotranslational protein degradation [37] Asc1 is required forefficient translation of short mRNAs with short open readingframes that usually show greater than average translationalefficiency in diverse eukaryotes [38] Asc1 is required toprevent frameshifting at ribosomes stalled at repeated CGA

codons In the absence of Asc1 ribosomes continue transla-tion at CGA codons but undergo substantial frameshiftingThus the general translation fidelity of the cell depends uponAsc1-mediated quality control [39] Taken together thesestudies indicate that Asc1 constitutes a ribosomal interface forsignal transduction and translational regulation [28]

32 Neurospora crassa N crassa is a model filamentousfungus [63] In N crassa cross-pathway control (CPC) wasfirst described by Carsiotis and collaborators [64 65] Thecross-pathway control in N crassa is the same as the GAACin S cerevisiae that is starvation for any one of severalamino acids leads to globally increased synthesis of enzymesof many amino acid biosynthetic pathways in this funguscpc-2 positively regulates the cross-pathway control underconditions of amino acid limitation [46] Therefore there isno activation of target amino acid biosynthetic genes in thecpc-2 mutant under starvation conditions (Table 1) Undernonstarved conditions mutation of the cpc-2 gene decreasesfungal growth Formation of protoperithecia during sexualreproduction is impaired in the cpc-2 mutant [47] Geneticepistasis between cpc-2 and components of the G proteinpathway has been studied [48] One Ga subunit (gna-3)is epistatic to cpc-2 during submerged-culture conidiationwhile two other G120572 subunits (gna-1 gna-2) are independentof cpc-2 and the G120573 (gnb-1) and G120574 (gng-1) subunits operate


downstream of cpc-2 during submerged-culture conidiationIn yeast two-hybrid assays gna-3 interacts with cpc-2 Theepistatic studies together with the protein-protein interactionstudies indicate that cpc-2 does work in the heterotrimeric Gprotein complex

4 Rack1 Proteins in Pathogenic Fungi

41 Candida albicans C albicans is an opportunisticpathogen and causes life-threatening systemic infections inimmunocompromised individuals [66] Its virulence factorsinclude host recognition biomolecules (adhesins) morpho-genetic transitions (the reversible transition between uni-cellular yeast cell and filamentous growth forms) biofilmssecreted aspartyl proteases and phospholipases [44 66]From transcriptomics and proteomics data Liu et alshow that the expression of ASC1 in C albicans is iron-temperature- and Gcn4-dependent and is downregulated byamino acid starvation caspofungin and farnesol (Table 1)[45] The asc1 null mutant displays shorter hyphae on severalliquid and solid hypha-inducing media compared to thewild-type strain [45] Adhesive growth and invasive growthare impaired in the asc1nullmutant [44]The asc1nullmutanthas attenuated virulence In a mouse model of systematicinfection the asc1 null mutant is dramatically less virulentthan the wild-type strain shown by the fact that 50 of themice infected with the asc1 null mutant survived while thewild-type strain killed all the infected mice In another assayusing a mouse model of disseminated infection nearly allof the mice inoculated with the wild-type strain died within16 days However mice infected with the asc1 null mutantwere completely asymptomatic [44] Finally Fan et al showthat transcription of adhesion-related genes ALS3 ECE1 andHWP1 [67] is reduced in the asc1 null mutant indicatingthat Asc1 regulates virulence of C albicans through theseimportant genes [44]

42 Aspergillus nidulans and Aspergillus fumigatus A nidu-lans a model filamentous fungus is also reported as anopportunistic pathogen [68 69] A fumigatus the majorcausative agent of life-threatening invasive aspergillosis inimmunocompromised individuals is a ubiquitous sapro-phytic fungus [70] Thermotolerance specialized cell wallmelanization resistance to oxidative stress and mycotoxins(gliotoxin) are important for virulence of A fumigatus Inaddition the cAMPPKA pathway regulates the synthesisof several virulence factors [71] In both A nidulans andA fumigatus Rack1 proteins CpcB play important rolesin fungal growth conidiation conidial germination andmycotoxin production (Table 1) [49 50] InA nidulans CpcBrepresses the cross-pathway control in the presence of aminoacids and regulates sexual development [50 52] Compared tothe wild-type strain the cpcBmutant ofA nidulans producesmuch fewer cleistothecia and the cleistothecia contain noascospores indicating that CpcB is required for proper for-mation of fruiting bodies and ascosporogenesis [50 52] InAfumigatus CpcB is localized in the cytoplasm To determinethe genetic relationship between CpcB and GpaB (Ga) thegpaB mutant and the double-deletion mutant cpcB gpaB

were generatedThedoublemutant cpcB gpaB causes a similarphenotype to the gpaBmutant with abnormal multiple septaconidiophores indicating the overlapping functions of CpcBand GpaB [49] Cell wall integrity of the cpcB mutantis impaired revealed by transmission electron microscopyexaminations [49] Virulence of the cpcBmutant is attenuatedin an immunosuppressed mouse model The study alsodemonstrates that the GndashH residues inWD repeats 1 2 and 3and theWndashD residue inWD repeat 2 of CpcB are required fornormal hyphal growth and conidiation and are also necessaryfor maintaining normal antifungal drug susceptibility ThecpcBmutant displays enhanced drug resistance which mightbe due to reduced intracellular drug accumulation and alteredergosterol component In addition the first GndashH residue ofCpcB plays a critical role in the virulence of A fumigatus[51]The involvement of CpcB in pathogenesis ofA fumigatusmight be through its connection with the G protein complexandor its role in maintaining proper cell wall structure

43 Cryptococcus neoformans C neoformans is an encapsu-lated yeast-like basidiomycetous fungus C neoformans hasa worldwide distribution [72] It is found in soil bird excre-ment and trees It is an opportunistic pathogen and causesmeningoencephalitis in immunocompromised individuals[73] Fungal capsulation andmelanization among others areimportant for its virulence The major virulence factors ofthe pathogen are regulated by the cAMPPKA pathway [53]In C neoformans the Rack1 protein Gib2 is required for fullvirulence (Table 1) [53ndash55] Gib2 functions as a scaffoldingadaptor protein and interacts with G120572 (Gpa1) and G120574 (Gpg1and Gpg2) proteins Gib2 also interacts with the proteinkinase C1 Smg1 a phosphodiesterase Pde2 and the small Gprotein Ras1 which are all involved in the cAMPPKA path-way Gib2 positively regulates the cAMPPKA pathway foroverexpression of Gib2 rescues the defects of the gpa1mutantin both melanization and capsule formation and restores thecAMP level by relieving the inhibitory effect of Ras1 on theadenylyl cyclase Cac1 in the gpa1mutant [54 55] In a murinemodel of cryptococcosis disruption of the GIB2 gene resultsin severe attenuation of virulence [54] In summary Gib2is involved in virulence by acting as a scaffolding adaptorprotein of the cAMPPKA pathway in C neoformans

44 Ustilago maydis U maydis a dimorphic basidiomycetecauses corn smut and serves as amodel for obligate biotrophicfungal pathogens [74] Infection of maize by U maydisrequires that haploid yeast cells of compatible mating typesfuse and establish dikaryotic filamentous hyphae The mor-phological transition from budding to filamentous hyphaeis important for fungal virulence and is regulated by theconserved cAMPPKA and MAPK pathways Loss of Rack1protein Rak1 causes slow growth hypersensitivity to cellwall stress attenuated cell fusion and attenuated virulencein U maydis (Table 1) [57] In infection assays more than80 of plants infected with the wild-type strain showedtumor formation but no tumors could be observed in rak1-infected maize plants Filament formation and appressoriumformation are impaired in the mutant The attenuated cell


fusion likely results from the reduced expression of rop1 atranscriptional activator of the pheromone response factor(prf1) that regulates pheromone (mfa) and pheromone-receptor genes Rak1 is a ribosome-associated protein andinteracts with a large number of proteins including 32ribosomal proteins shown in protein pull-down assaysTheseproteins are involved in metabolism energy productioncell division DNA replication rRNA processing and UDP-galactose translocation which are possibly involved in fungalpathogenesis [75] The constitutive expression of rop1 orconstitutive activation of the pheromone-responsive MAPKpathway could rescue the defect of the rak1 mutant inconjugation tube formation Prf1 is regulated at the post-transcriptional level by the cAMPPKA pathway and theMAPK pathway indicating that Rak1 possibly functions inthe cAMPPKA and MAPK pathways [74] However nointeraction between Rak1 and any G120572 subunits has beenestablished and additional studies are needed to determinehow Rak1 participates in the cAMPPKA and MAPK path-ways that are required for pathogenicity of U maydis

5 Concluding Remarks and Perspectives

Rack1 proteins play important roles in fungal pathogenesisHowever compared to the intensive studies onRack1 proteinsin human plants and yeasts [12 16 39] limited studieshave been conducted in a few pathogenic fungi In thesefungi Rack1 proteins affect various virulence factors throughconserved signal transduction pathways (Table 1) [76 77]In other fungal pathogens such as Penicillium marneffeiand Histoplasma capsulatum Rack1 proteins are found tobe associated with stress responses or dimorphic transition[78 79] In plant pathogens Fusarium verticillioides and Fgraminearum WD40 proteins are required for virulence andother important functions though the Rack1 proteins havenot been characterized [80] In addition protein-proteininteraction network analyses indicate thatWD40 proteins arehighly connected in the malaria parasite with 1928 potentialinteractions supporting the role of WD40-containing pro-teins including Rack1 proteins as hubs in cellular networks[81] Given the conserved and versatile roles of Rack1 proteinsin eukaryotes [34] it is important to explore the unique anddynamic roles of Rack1 proteins in different pathogenic fungi

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors thank Dr Brittany Anderton for critical readingof the manuscript

References

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[3] R Dean J A L Van Kan Z A Pretorius et al ldquoThe Top10 fungal pathogens in molecular plant pathologyrdquo MolecularPlant Pathology vol 13 no 4 pp 414ndash430 2012

[4] M Liu M D Healy B A Dougherty et al ldquoConserved fungalgenes as potential targets for broad-spectrum antifungal drugdiscoveryrdquo Eukaryotic Cell vol 5 no 4 pp 638ndash649 2006

[5] E Shor and N Chauhan ldquoA case for two-component signalingsystems as antifungal drug targetsrdquo PLoS Pathogens vol 11 no2 Article ID e1004632 2015

[6] L Li S J Wright S Krystofova G Park and K A BorkovichldquoHeterotrimeric G protein signaling in filamentous fungirdquoAnnual Review of Microbiology vol 61 pp 423ndash452 2007

[7] P Sassone-Corsi ldquoThe Cyclic AMP pathwayrdquo Cold SpringHarbor Perspectives in Biology vol 4 no 12 2012

[8] R E Chen and J Thorner ldquoFunction and regulation in MAPKsignaling pathways lessons learned from the yeast Saccha-romyces cerevisiaerdquo Biochimica et Biophysica ActamdashMolecularCell Research vol 1773 no 8 pp 1311ndash1340 2007

[9] D Mochly-Rosen H Khaner and J Lopez ldquoIdentification ofintracellular receptor proteins for activated protein kinase CrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 88 no 9 pp 3997ndash4000 1991

[10] D Ron C-H Chen J Caldwell L Jamieson E Orr andD Mochly-Rosen ldquoCloning of an intracellular receptor forprotein kinase C a homolog of the beta subunit of G proteinsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 91 no 3 pp 839ndash843 1994

[11] D R Adams D Ron and P A Kiely ldquoRACK1 a multifacetedscaffolding protein structure and functionrdquo Cell Communica-tion and Signaling vol 9 article 22 2011

[12] J-J Li andD Xie ldquoRACK1 a versatile hub in cancerrdquoOncogenevol 34 no 15 pp 1890ndash1898 2014

[13] T J Gibson ldquoRACK1 researchmdashships passing in the nightrdquoFEBS Letters vol 586 no 17 pp 2787ndash2789 2012

[14] S Gallo and N Manfrini ldquoWorking hard at the nexus betweencell signaling and the ribosomal machinery an insight into theroles of RACK1 in translational regulationrdquo Translation vol 3article e1120382 2015

[15] S Erbil O Oral G Mitou et al ldquoRACK1 is an interactionpartner of ATG5 and a Novel Regulator of Autophagyrdquo Journalof Biological Chemistry vol 291 no 32 pp 16753ndash16765 2016

[16] T Islas-Flores A Rahman H Ullah and M A VillanuevaldquoThe receptor for activated C kinase in plant signaling tale ofa promiscuous little moleculerdquo Frontiers in Plant Science vol 6article 1090 2015

[17] J-G Chen ldquoPhosphorylation of RACK1 in plantsrdquo Plant Signal-ing and Behavior vol 10 article e1022013 2015

[18] J C Miller W R Chezem and N K Clay ldquoTernary WD40repeat-containing protein complexes evolution compositionand roles in plant immunityrdquo Frontiers in Plant Science vol 6article 1108 2016

[19] Z Cheng J-F Li Y Niu et al ldquoPathogen-secreted proteasesactivate a novel plant immune pathwayrdquo Nature vol 521 no7551 pp 213ndash216 2015

[20] J Su J Xu and S Zhang ldquoRACK1 scaffolding a heterotrimericG protein and a MAPK cascaderdquo Trends in Plant Science vol20 no 7 pp 405ndash407 2015


[21] X Meng L Shan and P He ldquoStack heterotrimeric G proteinsandMAPK cascades on a RACKrdquoMolecular Plant vol 8 no 12pp 1691ndash1693 2015

[22] B L Kelly D B Stetson and RM Locksley ldquoLeishmaniamajorLACK antigen is required for efficient vertebrate parasitizationrdquoThe Journal of Experimental Medicine vol 198 no 11 pp 1689ndash1698 2003

[23] K G Rothberg D L Burdette J Pfannstiel N Jetton R Singhand L Ruben ldquoThe RACK1 homologue from Trypanosomabrucei is required for the onset and progression of cytokinesisrdquoJournal of Biological Chemistry vol 281 no 14 pp 9781ndash97902006

[24] D Cardenas P M Carter C S Nation et al ldquoLACK a RACK1ortholog facilitates cytochrome c oxidase subunit expression topromoteLeishmaniamajor fitnessrdquoMolecularMicrobiology vol96 no 1 pp 95ndash109 2016

[25] R SartorelloM J AmayaMHNathanson andCR SGarcialdquoThe plasmodium receptor for activated C kinase proteininhibits Ca2+ signaling in mammalian cellsrdquo Biochemical andBiophysical Research Communications vol 389 no 4 pp 586ndash592 2009

[26] B Hoffmann H-U Mosch E Sattlegger I B BarthelmessA Hinnebusch and G H Braus ldquoThe WD protein Cpc2p isrequired for repression of Gcn4 protein activity in yeast in theabsence of amino-acid starvationrdquoMolecular Microbiology vol31 no 3 pp 807ndash822 1999

[27] C E Zeller S C Parnell and H G Dohlman ldquoThe RACK1ortholog Asc1 functions as a G-protein 120573 subunit coupled toglucose responsiveness in yeastrdquo Journal of Biological Chemistryvol 282 no 34 pp 25168ndash25176 2007

[28] O Valerius M Kleinschmidt N Rachfall et al ldquoThe Sac-charomyces homolog of mammalian RACK1 Cpc2Asc1p isrequired for FLO11-dependent adhesive growth and dimor-phismrdquo Molecular and Cellular Proteomics vol 6 no 11 pp1968ndash1979 2007

[29] D Melamed L Bar-Ziv Y Truzman and Y Arava ldquoAsc1supports cell-wall integrity near bud sites by a Pkc1 independentmechanismrdquo PLoS ONE vol 5 no 6 Article ID e11389 2010

[30] F C Galvao D Rossi W D S Silveira S R Valentini and CF Zanelli ldquoThe deoxyhypusine synthase mutant dys1-1 revealsthe association of eIF5A and Asc1 with cell wall integrityrdquo PLoSONE vol 8 article e60140 2013

[31] N Rachfall K Schmitt S Bandau et al ldquoRACK1Asc1p aribosomal node in cellular signalingrdquo Molecular and CellularProteomics vol 12 no 1 pp 87ndash105 2013

[32] S A Chasse P Flanary S C Parnell et al ldquoGenome-scale anal-ysis reveals Sst2 as the principal regulator of mating pheromonesignaling in the yeast Saccharomyces cerevisiaerdquo Eukaryotic Cellvol 5 no 2 pp 330ndash346 2006

[33] J M Tkach A Yimit A Y Lee et al ldquoDissecting DNAdamage response pathways by analysing protein localizationand abundance changes during DNA replication stressrdquoNatureCell Biology vol 14 no 9 pp 966ndash976 2012

[34] V R Gerbasi C M Weaver S Hill D B Friedman and AJ Link ldquoYeast Asc1p and mammalian RACK1 are functionallyorthologous core 40S ribosomal proteins that repress geneexpressionrdquo Molecular and Cellular Biology vol 24 no 18 pp8276ndash8287 2004

[35] L Jenner S Melnikov N G de Loubresse et al ldquoCrystalstructure of the 80S yeast ribosomerdquo Current Opinion inStructural Biology vol 22 no 6 pp 759ndash767 2012

[36] S M Coyle W V Gilbert and J A Doudna ldquoDirect linkbetween RACK1 function and localization at the ribosome invivordquo Molecular and Cellular Biology vol 29 no 6 pp 1626ndash1634 2009

[37] K Kuroha M Akamatsu L Dimitrova et al ldquoReceptor foractivated C kinase 1 stimulates nascent polypeptide-dependenttranslation arrestrdquo EMBO Reports vol 11 no 12 pp 956ndash9612010

[38] M K Thompson M F Rojas-Duran P Gangaramani and WV Gilbert ldquoThe ribosomal protein Asc1RACK1 is required forefficient translation of short mRNAsrdquo eLife vol 5 Article IDe11154 2016

[39] A SWolf and E J Grayhack ldquoAsc1 homolog of humanRACK1prevents frameshifting in yeast by ribosomes stalled at CGAcodon repeatsrdquo RNA vol 21 no 5 pp 935ndash945 2015

[40] M McLeod B Shor A Caporaso W Wang H Chen and LHu ldquoCpc2 a fission yeast homologue of mammalian RACK1protein interacts with Ran1 (Pat1) kinase to regulate cell cycleprogression and meiotic developmentrdquo Molecular and CellularBiology vol 20 no 11 pp 4016ndash4027 2000

[41] Y Tarumoto J Kanoh and F Ishikawa ldquoReceptor for activatedC-kinase (RACK1) homolog Cpc2 facilitates the general aminoacid control response through Gcn2 kinase in fission yeastrdquoThe Journal of Biological Chemistry vol 288 no 26 pp 19260ndash19268 2013

[42] A Nunez A Franco M Madrid et al ldquoRole for RACK1orthologue Cpc2 in the modulation of stress response in fissionyeastrdquo Molecular Biology of the Cell vol 20 no 18 pp 3996ndash4009 2009

[43] A Nunez A Franco T Soto J Vicente M Gacto and JCansado ldquoFission yeast receptor of activated C kinase (RACK1)ortholog Cpc2 regulates mitotic commitment through Wee1kinaserdquoThe Journal of Biological Chemistry vol 285 no 53 pp41366ndash41373 2010

[44] SWKimY J Joo and J Kim ldquoAsc1p a ribosomal protein playsa pivotal role in cellular adhesion and virulence in Candidaalbicansrdquo Journal of Microbiology vol 48 no 6 pp 842ndash8482010

[45] X Liu X Nie Y Ding and J Chen ldquoAsc1 aWD-repeat proteinis required for hyphal development and virulence in Candidaalbicansrdquo Acta Biochimica et Biophysica Sinica vol 42 no 11pp 793ndash800 2010

[46] D Kruger J Koch and I B Barthelmess ldquocpc-2 a new locusinvolved in general control of amino acid synthetic enzymes inNeurospora crassardquo Current Genetics vol 18 no 3 pp 211ndash2151990

[47] F Muller D Kruger E Sattlegger et al ldquoThe cpc-2 gene ofNeurospora crassa encodes a protein entirely composed ofWD-repeat segments that is involved in general amino acid controland female fertilityrdquo MGG Molecular amp General Genetics vol248 no 2 pp 162ndash173 1995

[48] A V Garud The role of the cross pathway control (cpc)-2gene in the filamentous fungus Neurospora crassa [MS thesis]University of California Riverside Calif USA 2013

[49] Z-D Cai Y-F Chai C-Y Zhang W-R Qiao H Sang and LLu ldquoThe G120573-like protein CpcB is required for hyphal growthconidiophore morphology and pathogenicity in Aspergillusfumigatusrdquo Fungal Genetics and Biology vol 81 pp 120ndash1312015

[50] Q Kong L Wang Z Liu N-J Kwon S C Kim and J-H YuldquoG120573-like CpcB plays a crucial role for growth and development


of Aspergillus nidulans and Aspergillus fumigatusrdquo PLoS ONEvol 8 article e70355 2013

[51] Z Cai Y Chai C Zhang R Feng H Sang and L LuldquoMolecular characterization of G120573-like protein CpcB involvedin antifungal drug susceptibility and virulence in A fumigatusrdquoFrontiers in Microbiology vol 7 article 106 2016

[52] B Hoffmann C Wanke S K LaPaglia and G H Braus ldquoc-Jun and RACK1 homologues regulate a control point for sexualdevelopment in Aspergillus nidulansrdquo Molecular Microbiologyvol 37 no 1 pp 28ndash41 2000

[53] J Choi W H Jung and J W Kronstad ldquoThe cAMPproteinkinase A signaling pathway in pathogenic basidiomycete fungiconnections with iron homeostasisrdquo Journal of Microbiologyvol 53 no 9 pp 579ndash587 2015

[54] Y Wang G Shen J Gong et al ldquoNoncanonical G120573 Gib2 isa scaffolding protein promoting camp signaling through func-tions of ras1 and cac1 proteins in cryptococcus neoformansrdquoTheJournal of Biological Chemistry vol 289 no 18 pp 12202ndash122162014

[55] D A Palmer J KThompson L Li A Prat and PWang ldquoGib2a novel G120573-likeRACK1 homolog functions as a G120573 subunit incAMP signaling and is essential in Cryptococcus neoformansrdquoThe Journal of Biological Chemistry vol 281 no 43 pp 32596ndash32605 2006

[56] R Ero V TDimitrova Y Chen et al ldquoCrystal structure ofGib2a signal-transducing protein scaffold associated with ribosomesin Cryptococcus neoformansrdquo Scientific Reports vol 5 article8688 2015

[57] LWang P Berndt X Xia J Kahnt and R Kahmann ldquoA seven-WD40 protein related to human RACK1 regulates mating andvirulence in Ustilago maydisrdquo Molecular Microbiology vol 81no 6 pp 1484ndash1498 2011

[58] K Tarnowski K Fituch R H Szczepanowski M Dadlez andM Kaus-Drobek ldquoPatterns of structural dynamics in RACK1protein retained throughout evolution a hydrogen-deuteriumexchange study of three orthologsrdquo Protein Science vol 23 no5 pp 639ndash651 2014

[59] B J Haas S Kamoun M C Zody et al ldquoGenome sequenceand analysis of the Irish potato famine pathogen Phytophthorainfestansrdquo Nature vol 461 no 7262 pp 393ndash398 2009

[60] B M Tyler S Tripathy X Zhang et al ldquoPhytophthora genomesequences uncover evolutionary origins and mechanisms ofpathogenesisrdquo Science vol 313 no 5791 pp 1261ndash1266 2006

[61] A G Hinnebusch ldquoTranslational regulation of GCN4 andthe general amino acid control of yeastrdquo Annual Review ofMicrobiology vol 59 pp 407ndash450 2005

[62] C J Decker and R Parker ldquoP-bodies and stress granules possi-ble roles in the control of translation and mRNA degradationrdquoCold Spring Harbor Perspectives in Biology vol 4 no 9 ArticleID a012286 2012

[63] J E Galagan S E Calvo K A Borkovich et al ldquoThe genomesequence of the filamentous fungus Neurospora crassardquo Naturevol 422 no 6934 pp 859ndash868 2003

[64] M Carsiotis and A M Lacy ldquoIncreased activity of trypto-phan biosynthetic enzymes in histidine mutants of neurosporacrassardquo Journal of Bacteriology vol 89 pp 1472ndash1477 1965

[65] M Carsiotis R F Jones and A C Wesseling ldquoCross-pathwayregulation histidine-mediated control of histidine tryptophanand arginine biosynthetic enzymes in Neurospora crassardquo Jour-nal of Bacteriology vol 119 no 3 pp 893ndash898 1974

[66] F L Mayer D Wilson and B Hube ldquoCandida albicanspathogenicity mechanismsrdquoVirulence vol 4 no 2 pp 119ndash1282013

[67] Y Fan H He Y Dong and H Pan ldquoHyphae-specific genesHGC1 ALS3 HWP1 and ECE1 and relevant signaling pathwaysin Candida albicansrdquo Mycopathologia vol 176 no 5 pp 329ndash335 2013

[68] J E Galagan S E Calvo C Cuomo et al ldquoSequencing ofAspergillus nidulans and comparative analysis withA fumigatusand A oryzaerdquo Nature vol 438 no 7071 pp 1105ndash1115 2005

[69] B H Segal E S DeCarlo K J Kwon-Chung H L MalechJ I Gallin and S M Holland ldquoAspergillus nidulans infectionin chronic granulomatous diseaserdquo Medicine vol 77 no 5 pp345ndash354 1998

[70] K J Kwon-Chung and J A Sugui ldquoAspergillus fumigatus-whatmakes the species a ubiquitous human fungal pathogenrdquo PLoSPathogens vol 9 no 12 Article ID e1003743 pp 1ndash4 2013

[71] T M Hohl and M Feldmesser ldquoAspergillus fumigatus princi-ples of pathogenesis and host defenserdquo Eukaryotic Cell vol 6no 11 pp 1953ndash1963 2007

[72] B J Loftus E Fung P Roncaglia et al ldquoThe genome ofthe basidiomycetous yeast and human pathogen Cryptococcusneoformansrdquo Science vol 307 no 5713 pp 1321ndash1324 2005

[73] X Lin and J Heitman ldquoThe biology of the Cryptococcusneoformans species complexrdquo Annual Review of Microbiologyvol 60 pp 69ndash105 2006

[74] T Brefort G Doehlemann A Mendoza-Mendoza S Reiss-mann A Djamei and R Kallmann ldquoUstilago maydis as apathogenrdquo Annual Review of Phytopathology vol 47 pp 423ndash445 2009

[75] L Wang Functional characterization of a seven-WD40 repeatprotein Rak1 in Ustilago maydis [PhD thesis] Philipps-Universitat Marburg 2011

[76] D Turra D Segorbe andADi Pietro ldquoProtein kinases in plant-pathogenic fungi conserved regulators of infectionrdquo AnnualReview of Phytopathology vol 52 pp 267ndash288 2014

[77] G Li X Zhou and J-R Xu ldquoGenetic control of infection-related development in Magnaporthe oryzaerdquo Current Opinionin Microbiology vol 15 no 6 pp 678ndash684 2012

[78] M S Winters D S Spellman Q Chan et al ldquoHistoplasmacapsulatum proteome response to decreased iron availabilityrdquoProteome Science vol 6 article 36 2008

[79] J M Chandler E R Treece H R Trenary et al ldquoProteinprofiling of the dimorphic pathogenic fungus Penicilliummarneffeirdquo Proteome Science vol 6 article 17 2008

[80] W-B Shim U S Sagaram Y-E Choi J So H H Wilkinsonand Y-W Lee ldquoFSR1 is essential for virulence and female fer-tility in Fusarium verticillioides and F graminearumrdquoMolecularPlant-Microbe Interactions vol 19 no 7 pp 725ndash733 2006

[81] P Chahar M Kaushik S S Gill et al ldquoGenome-wide colla-tion of the Plasmodium falciparum WDR protein superfamilyreveals malarial parasite-specific featuresrdquo PLoS ONE vol 10article e0128507 2015

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


for the binding of other proteins [11] Rack1 proteins areconstitutively expressed in eukaryotes Rack1 has been inten-sively studied in mammalian cells [12 13] Rack1 functionsin angiogenesis tumor growth cell migration apoptosisautophagy neuronal response proper function of the circa-dian clock defense responses against virus infection chro-matin remodeling transcriptional and translational regula-tions and cAMPPKA and MAPK pathways [11ndash15] Rack1regulates these biological processes through the control ofprotein complex assembly [13] In plants Rack1 proteins arefunctional in seed germination leaf production floweringhormonal signaling and bioticabiotic stress responses [16ndash18] The emerging role of Rack1 as a scaffold protein in theMAPK pathway in Arabidopsis thaliana has been recentlypublished [19ndash21] In protozoan parasites Rack1 proteins arecritical for effective mammalian parasitization by Leishmaniamajor and Trypanosoma brucei which cause leishmaniasisand African trypanosomiasis respectively [22ndash24] The Lmajor LACK (Leishmania homologue of mammalian RACK)antigen is also a target of the immune response in mice andtherefore a vaccine candidate for human leishmaniasis [22]In Plasmodium falciparum the most lethal malarial parasitethe Rack1 protein inhibits Ca2+ signaling of the mammaliancells and subverts the host intracellular environment animportantmechanism for parasite survival [25] In summaryRack1 proteins play important roles across a wide variety oforganisms In this review we summarize recent progress onRack1 proteins in model and pathogenic fungi

2 Rack1 Homologs Are Well Conserved

The Rack1 protein is found in many organisms including thealga Chlamydomonas reinhardtii yeasts filamentous fungiplants nematodes insects and vertebrates indicating that itis evolutionarily conserved [16 58] In fungi Rack1 proteinsare well conserved in most species of ChytridiomycotaZygomycota Glomeromycota Ascomycota and Basidiomy-cota (Figure 1) Rack1 proteins are also well conserved infungi-like microbes oomycetes which cause serious plantdiseases such as potato late blight and sudden oak death[59 60]

Rack1 proteins are functionally conserved Multiple com-plementation assays show that Rack1 proteins are func-tionally interchangeable among different species or evenacross kingdoms [26 49 52] For example the mammalianRACK1 gene can rescue the defects of rack1 mutants inSchizosaccharomyces pombe andAspergillus nidulans [40 52]The Neurospora crassa cpc-2 and the rat RACK1 genes areable to complement the cpc2mutant in S pombe [26] RACK1genes of A nidulans and yeasts (S cerevisiae S pombeand Candida albicans) can largely rescue the hyphal growthdefects of the cpcB deletion mutant in Aspergillus fumigatus[49] Species-specific roles of Rack1 proteins have also beenshown in different fungi For example the A nidulans CpcBortholog but not theRACK1 genes from yeasts can completelyrescue the conidiation defect of theA fumigatus cpcBmutant[49] Taken together these studies show the well conservedand unique roles of Rack1 proteins in different fungal species

3 Rack1 Proteins in Model Fungi

31 Saccharomyces cerevisiae In S cerevisiae a modelunicellular eukaryote the Rack1 homolog known as Asc1is involved in multiple biological processes (Table 1) Asc1is involved in the general amino acid control (GAAC) thatprovides the cell with sufficient amounts of protein precursorsunder conditions of amino acid limitation [61] Amino acidstarvation in yeast promotes translation of GCN4 whichthen causes expression of genes required for synthesis ofall 20 amino acids This response is called GAAC In theabsence of amino acid starvation Asc1 represses Gcn4 [26]a transcription activator of the GAAC pathway [61] InS pombe studies suggest that Cpc2 promotes the GAACresponse under the amino acid starvation condition [41]

Asc1 functions as the G120573 subunit for Gpa2 and inter-acts directly with the G120572 subunit as a guanine nucleotidedissociation inhibitor that inhibits the guanine nucleotideexchange activity of G120572 Asc1 negatively regulates glucose-mediated signaling via two pathways In the cAMPPKApathway Asc1 binds to the effector enzyme adenylyl cyclase(Cyr1) in addition to Gpa2 and represses the production ofcAMP in response to glucose stimulation [27] Secondly Asc1is involved in the Kss1MAPK pathway by binding to Ste20 Inthe asc1 mutant basal phosphorylation of Kss1 is enhancedSimilarly under pheromone stimulus the asc1mutant showsenhanced phosphorylation of both Fus3 and Kss1 but showsreduced expression of gene FLO11 key components forpheromone responsemating andfilamentous growth [8 28]

Asc1 is involved in cell wall integrity and stress responses[28ndash31] The asc1 mutant is hypersensitive to cell wall dam-aging agents iron chelators and nitrosative stress [29 31]Similarly Cpc2 is involved in stress responses in S pombe[42] The cell wall integrity defect of the asc1 mutant mostlikely results from PKC-independent mechanisms becausethe double-knockout mutant (asc1 pkc1) shows synergisticsensitivity to cell wall stresses [29] Interestingly the basalphosphorylation level of the MAPK Slt2 is higher in theasc1 mutant [32] indicating that Asc1 regulates the SLT2MAPKpathway In addition Asc1 regulates replication stress-induced formation of P-bodies that consist of many enzymesinvolved in mRNA turnover [33 62] Asc1 also regulates cellsize Compared to the wild-type control the cell size of theasc1 mutant is larger in S cerevisiae [28] The enlarged cellsize is also observed in the cpc2mutant in S pombe [43]

Asc1 executes its many functions by interacting withdifferent proteins and regulating the transcription and trans-lation of different genes De novo proteome analysis indi-cates that the asc1 mutant shows 50 elevated de novobiosynthesis of soluble proteins compared to the wild typeIn contrast expression of insoluble proteins is reduced bynearly a quarter in the asc1 mutant [31] The protein levelof several transcription factors including Rap1 Tec1 Phd1and Flo8 is downregulated but the protein level of Ste12 isupregulated over 6-fold in the asc1mutant [31] Interestinglyall three transcription factors Flo8 Ste12 and Tec1 positivelyregulate the expression of gene FLO11 Flo8 and Tec1 aredownregulated and Ste12 is upregulated in the asc1 mutantHowever the expression of gene FLO11 is still downregulated




AnimalsPlants

TTric

hoto

my

Oomycetes

Basidiomycetes

Protozoa

1000

1000

325

501

990

512

359

1000

904

929

856

655

868

820

1000

493

1000

975

1000

689

998

1000

601

995

980

1000

357

977383

932949

713 555

894 496

1000

802

353

504

466

379

977

989

Ago

Sce

Ssc

Bci

Sma

Ncr

BbaMro

Cor

FgrFveG

gr

Fox

Cal

Spo

HsaMmu

Dme

CelAthOsaCrePraPi

nPsoH

arLma

BdeRir

Mci

Cci

Sco

Mla

Pgr

Cne

Uma

Afu

Acl

Afl

Aor

Ang

Ani

Hca

Mgr

Mor

Tbr








[8 26ndash39]



[40ndash43]







[50 52]

Basidiomycetes





















Competing Interests


Acknowledgments


References




























































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




AnimalsPlants

TTric

hoto

my

Oomycetes

Basidiomycetes

Protozoa

1000

1000

325

501

990

512

359

1000

904

929

856

655

868

820

1000

493

1000

975

1000

689

998

1000

601

995

980

1000

357

977383

932949

713 555

894 496

1000

802

353

504

466

379

977

989

Ago

Sce

Ssc

Bci

Sma

Ncr

BbaMro

Cor

FgrFveG

gr

Fox

Cal

Spo

HsaMmu

Dme

CelAthOsaCrePraPi

nPsoH

arLma

BdeRir

Mci

Cci

Sco

Mla

Pgr

Cne

Uma

Afu

Acl

Afl

Aor

Ang

Ani

Hca

Mgr

Mor

Tbr








[8 26ndash39]



[40ndash43]







[50 52]

Basidiomycetes





















Competing Interests


Acknowledgments


References




























































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology







[8 26ndash39]



[40ndash43]







[50 52]

Basidiomycetes





















Competing Interests


Acknowledgments


References




























































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology













Competing Interests


Acknowledgments


References




























































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





Competing Interests


Acknowledgments


References




























































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology









































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Documents

Review Article Roles of Rack1 Proteins in Fungal Pathogenesis