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DUBs at a glanceKeith D. WilkinsonDepartment of Biochemistry, Emory UniversitySchool of Medicine, Atlanta, GA 30322, USAe-mail: [email protected]
Journal of Cell Science 122, 2325-2329Published by The Company of Biologists 2009doi:10.1242/jcs.041046
IntroductionThe discovery of protein ubiquitylationthree decades ago was the beginning of ourunderstanding of a new mechanism bywhich proteins are marked for assemblyinto macromolecular complexes ormovement between cellular compartments.The finding that ubiquitylation (thecovalent attachment of the small proteinubiquitin to other proteins) targetedproteins for degradation earned AvramHershko, Aaron Ciechanover and Irwin
Rose the Nobel Prize in Chemistry in 2004(Wilkinson, 2004). This early workspawned a large number of studies thatinvestigated the role of ubiquitin andseveral other ubiquitin-like proteins(UBLs) as targeting signals in virtually allaspects of cellular protein metabolism(Chen, 2005; Cohn and D’Andrea, 2008;Saksena et al., 2007; Weake and Workman,2008). The best understood example ofubiquitylation is the marking of proteinsfor delivery to the 26S proteasome,resulting in their degradation (Chiba andTanaka, 2004; Guo et al., 2007; Hershkoand Ciechanover, 1998; Schwartz andHochstrasser, 2003; Varshavsky et al.,1989).
Similar to all regulated targeting pathways,the process of ubiquitylation is reversible.The enzymes that reverse the modificationof proteins by ubiquitin are collectivelyknown as deubiquitylating enzymes
(DUBs) (Amerik and Hochstrasser, 2004;D’Andrea and Pellman, 1998; Wilkinson,1997). Enzymes that reverse themodification by UBLs are similarlynamed: desumoylating enzymes removeSUMO (small ubiquitin-related modifier),deneddylating enzymes remove NEDD8(neural precursor cell expressed,developmentally downregulated 8) and de-ISGylating enzymes remove ISG15(interferon-stimulated gene product 15).
There are many fine reviews describing thecomplex enzymatic mechanisms thatregulate the conjugation of ubiquitin andUBLs to target proteins; the reader isreferred to these for details of theubiquitylation machinery (Belgareh-Touzeet al., 2008; Dye and Schulman, 2007;Hochstrasser, 2007; Starita and Parvin,2006). Briefly, ubiquitin is first thiol-esterified at its C-terminus by the action ofthe E1 ubiquitin-activating enzyme and
2325Cell Science at a Glance
(See poster insert)
DUBs at a GlanceKeith D. Wilkinson
© Journal of Cell Science 2009 (122, pp. 2325-2329)
Abbreviations: 2A-DUB, histone H2A deubiquitinase; ABRA1, abraxas protein forming a complex required for double-strand-break DNA repair; AMSH, associated molecule with the SH3 domain of STAM; APC/C, anaphase-promoting complex/cyclosome [activity requires co-activators Cdc20 (cell division cycle 20) or Cdh1 (Cdc20 homolog 1) whose identity is shown as a superscript]; ATM, ataxia telangiectasia, mutated homolog; BARD1, BRCA1-associated RING domain 1 (heterodimerizes with BRCA1 to form an active ubiquitin ligase); BRCA1, breast cancer 1 tumor suppressor; BRCC36, BRCA1/BRCA2-containing complex subunit 36; βTrCP, β-transducin repeat-containing homolog protein; Cbl, Casitas B-lineage lymphoma; Cdk, cyclin-dependent kinase; Chk2, checkpoint kinase 2; DUB, deubiquitylating enzyme; E1, a ubiquitin-activating enzyme; E2, a ubiquitin-conjugating enzyme; E3, a ubiquitin ligase; FANCD2, product of the Fanconi anemia, complementation group D2 gene; FOXO, forkhead transcription factor O; H2A, histone H2A; H2B, histone H2B; H2AX, histone H2AX; H3, histone H3; HIF-1α, hypoxia-inducible factor 1α; IκB, inhibitor of NF-κB; ISG15, product of the interferon-stimulated gene 15; JAMM, a DUB family of proteins with the Jab1/MPN metalloenzyme domain (Pfam PF01398, EC 3.1.2.15); L, ligand; MAD2, mitotic arrest-deficient 2 protein inhibitor of APC/CCdc20; MDM2, murine double minute 2; MDMX, MDM2-like p53-binding protein; MJD, a DUB family of proteins with the Machado-Joseph Disease protein domain (Pfam PF02099, EC 3.4.22.-); MLL3, myeloid/lymphoid or mixed-lineage leukemia protein 3 complex; Myc, a transcripion
factor that is a homolog of the Myelocytomatosis viral oncogene; Nedd8, neural precursor cell expressed, developmentally downregulated 8; NEMO, NF-κB essential modulator; NF-�B, nuclear factor-κB; OTU, a DUB family of proteins with the ovarian tumor domain (Pfam PF02338, EC 3.1.2.-); PCAF, p300/CBP-associated factor; PCNA, proliferating cell nuclear antigen; Plk1, polo-like kinase 1; POH1, DUB of the 19S lid complex; Pol η, DNA polymerase eta; ProUb, the pro-protein gene products of ubiquitin-encoding genes; pVHL, von Hippel-Lindau tumor suppressor; RAD, radiation sensitive (genes required for DNA repair functions); RAP80, required for double-strand-break DNA repair; Rb, retinablastoma tumor suppressor; RIP1, receptor-interacting protein 1; SAGA, Spt-Ada-Gcn5-acetyltransferase complex; SCF, a class of ubiquitin ligases consisting of Skp1, a cullin and an F-box protein whose identity is indicated by a superscript; SENP, a family of human SUMO- or Nedd8-specific proteses with the ubiquitin-like protease domain (Pfam PF02902, EC 3.4.22); SUMO, small ubiquitin-related modifier; TAB2/3, TAK1-binding protein 2/3; TAK1, TGFβ-activated kinase 1; TF, transcription factor; TNF, tumor necrosis factor; TRAF, TNF receptor-associated factor; UAF1, USP1-associated factor 1; Ub, ubiquitin; Ubc13/Uev1, heterodmeric E2 ubiquitin-conjugating enzyme that synthesizes K63-linked polyubiquitin chains; UCH, a DUB family of proteins with the ubiquitin C-terminal hydrolase domain (Pfam PF01088, EC,3.4.19.12); USP, a DUB family of proteins with the ubiquitin-specific protease domain (Pfam PF00443, EC 3.1.2.15).
Deubiquitylating (isopeptidase)
Deneddylating
DeISGylating
Desumoylating
UbPolyUb
Nedd8
ISG15
Ub
Nedd8
UbPolyUb PolyUb
Nedd8 Nedd8
SUMO
PolyUb
USP UCH OTU JAMM MJD SENP
Substrate-specificity of protease familiesacting on ubiquitin-like proteins
K63-specific DUBsin NF-�B signaling
IκBNF-κB
IκBNF-κB
NF-κB
RIP1
LigandReceptor
E1, Ubc13/Uev1A
ATP
A20, CYLD
A20
CYLD, A20
ProteasomeβTrCP ATP
Peptides
NEMO
βα
NEMO
TA
K1
TA
B2/3
APC/CpCdh1
APC/CCdc20
APC/C
M
G2
S
G1
APC/CCdh1
APC/CpCdh1
BAP1 USP3
Proteolysis
Checkpoint
DNA damage
DUBs remodel and disassemblepolyubiquitin chains
Protein
ProUb Ub Ubiquitylatedprotein
Receptor
PolyUb Alteredlocalization,
binding,stability or
activity
E1,E2,E3
ProUb
E1,E2,E3
Substrate
Multiple DUBs?
USP5
USP14UCH37
UCH37
POH1
POH1
USP14
Proteasome
Lid
Base
19Sregulator
αββα
20Sprotease
DUBs both stimulateand inhibit proteolysis
MultipleDUBs?
K48-linked polyubiquitin
K63-linked polyubiquitin
Monoubiquitin
Reaction
Influence
DUB activity
AMSH
Cbl
LL
L
L
AMSH?
AMSH?
USP8Early endosome
Multivesicular bodyLysosome
K63-linked ubiquitin used inendocytosis and cargo sorting
DUBs regulate DNA repair and the stability of multiple proteins at cell-cycle checkpoints
H2B
H2A
USP7•GMP synthetase
USP22•SAGASAGA
2A-DUB•PCAF
USP3
USP21
USP16
H2BTF-
Corepressor-
S10-P
Aurora B
assoc. Ub ligases MLL3
assoc. Ub ligases
H3
H3
H3
H2A
Deubiquitylation of histones regulatestranscription and chromatin dynamics
Elongation andtermination
Silencing and chromatincondensation
USP44
Chromosome attachment
p31
UbiquitylatedAPC/CCdc20
MAD2•APC/CCdc20
MAD2
(Inactive) (Active)
APC/CCdc20
Ub-protein
Cell-cycle arrest
Cdk2/Cyclin E
p21CIP/WAF1
P53 MDMX/MDM2
MDM2
USP7 USP7
USP7
MDMXATM, CHK2
pMDMX
p53-mediated arrest
USP3 BRCA1/BARD1 Double-strand-breakrepair
X
ABRA1
Brcc36
RAP 80
Double-strand-break DNA repair
?
FANCD2 FANCD2
USP1/UAF1
RAD5, Ubc13/Uev1
RAD18RAD6
PCNA-boundleision
USP1degradation
Pol η
Crosslink repair
Error-free synthesis
Translesionsynthesis
PCNA-mediated DNA repair
Ub-Plk1
Ub-Wee1
Ub-Claspin
Ub-Claspin Ub-
Cyclin EUb-Myc
Cdc14B
APC/CCdh1
SCFβTrcp
Wee1
p-Wee1
USP28?
?
? USP28
Plk1 Cdk1-cyclin B1
pCdk1-cyclin B1
Cdc25 phosphatase
pCdk2-cyclin E
Cdk2-cyclin E
MycClaspin
SCFFbw7α
p
USP28Claspin
Cdc25-mediated checkpoint arrest
G2/Mtransition G2 block S block S-phase
progressionProliferation
and apoptosis
Initiation oftranscription
Substrate
Substrate
TRAFcomplex
TRAFcomplex
H2AX H2AX
KEY
DUB protein familyActivity
K4-Me3
A20
Ataxin-3
BAP1, USP11
CYLD
DUB1, DUB2
UCH-L1
USP1
USP2A
USP4
USP6/TRE17
USP7/HAUSP
UBP14
USP33/VDU1,USP20/VDU2
Ub ligase and DUB for RIP1
K63-linked polyubiquitin
?
K63-ubiquitylated TRAFs, RIP1, others
Common cytokine receptor,gamma chain
?
PCNA, FANCD2
Fatty acid synthesase?MDM2?
Rb? Ro52 ubiquitin ligase
?
p53, MDM2, FOXO
Proteasome-boundpolyubiquitin
pVHL ubiquitin ligase
Deletion causes prolonged NF-κBresponses and inflammation
Polyglutamine repeat expansion causestype 3 Spinal Cerebellar Ataxia
BRCA1/2 DNA-repair pathways; cancer
Mutation causes benign tumors and failure todownregulate NF-κB and JNK signaling
Overexpression increases substrate half-life, prolongs cytokine response
Mutation causes gracile axonal dystrophy in mice;accumulated in neuronal inclusion bodies in humans
Mutated in Fanconi Anemia; involved in DNA repair
Involved in prostate cancer;protects from apoptosis
Oncoprotein linked to lung cancerand Sjogren’s syndrome
Oncogenic when overexpressed from17p13 translocations
Role in DNA repair and oxidativestress response
Mutated in ataxic mouse;ubiquitin depletion phenotype
Regulation of HIF-1α; role in angiogenesisand metastasis
βα
Spindle checkpoint
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then is subsequently transferred to one ofseveral E2 ubiquitin-conjugating enzymesthat act as carrier proteins. Finally,ubiquitin is transferred to a lysine residueof the target protein through the combinedaction of the E2-ubiquitin thiol ester andone of hundreds of E3 ubiquitin ligases.The ubiquitylation signal that is attachedcan consist of a single ubiquitin, multipleubiquitins or a polyubiquitin chain inwhich successive ubiquitin molecules areassembled by the ubiquitylation ofubiquitin itself (Baboshina and Haas, 1996;Chau et al., 1989; Hofmann and Pickart,1999; Koegl et al., 1999; Tokunaga et al.,2009; Wu-Baer et al., 2003). Because anyof the seven lysine residues of ubiquitin, orits amino terminus, can be modified bya subsequent ubiquitin to form apolyubiquitin chain, there is a hugevariation in the structure of polyubiquitinsignals that can be attached. Apolyubiquitin chain can involve linkages tothe same lysine residue on each ubiquitinmoiety to yield a homogeneous chain, or itcan involve linkages to different lysineresidues on different ubiquitin moeities,which results in a heterogeneous linear orbranched chain.
Ubiquitylation is a versatile and dynamictargeting signal. The use of a protein, ratherthan a small molecule, to modify a targetprotein confers a large interaction surfacethat can be recognized by specificreceptors. In addition, the many differentpolymeric forms of ubiquitin allow forstructural variation of the signal.Structurally different forms ofpolyubiquitin are thought to target proteinsfor different cellular fates. For example,early work showed that K48-, K29-, andK11-linked polyubiquitin chains can targetproteins for degradation by the proteasome(Chau et al., 1989; Jin et al., 2008; Koeglet al., 1999); K63-linked polyubiquitinchains participate in DNA repair andsignaling kinase complexes (Deng et al.,2000; Spence et al., 1995); monoubiquitinand K63-linked chains are involved intargeting cell-surface proteins forinternalization and endosomal sorting(Hicke and Riezman, 1996; Springaelet al., 1999); and monoubiquitylation ofhistones can influence chromatin structureand transcription (Levinger andVarshavsky, 1980). Recent massspectrometry analysis of ubiquitylatedproteins shows that chains with multiplelinkages can be attached to a single protein(Bish et al., 2008; Crosas et al., 2006; Kim
et al., 2007; Kirkpatrick et al., 2005;Mayor et al., 2005; Xu and Peng, 2008),although the specific pathways in whichthese more complex polyubiquitin chainsare involved remain poorly understood.
In this article and its accompanying poster,I summarize our understanding of themetabolic function of DUBs and discusstheir roles in regulating several ubiquitin-dependent processes. Here, I use the termDUBs to refer only to those enzymes thatact on ubiquitin. Much less is knownabout the enzymes that act on UBLs (Hay,2007; Love et al., 2007; Mikolajczyket al., 2007; Reverter et al., 2005;Sulea et al., 2006) and they will not bediscussed here. Although much of what isknown about DUBs was first observed inyeast, the yeast pathways or enzyme namesare not emphasized. The poster illustratesthe role of over 20 of nearly 100mammalian DUBs that act on ubiquitin(Nijman et al., 2005), and concentrates onthe DUBs about which something isknown regarding their physiology orpathology. For pathways where thesubstrate or the process regulated is knownin some detail, specific examples areprovided. It should be noted that a role forDUBs has been implied in many othercontexts, such as apoptosis, Parkinson’sdisease and neuronal-inclusion-bodydiseases, although in many cases theprecise DUB involved has not beenidentified. Space limitations restrict theinclusion of these aspects in the poster.
DUBs are numerous and specificThe nearly 100 putative mammalian DUBsare grouped into five different families(Amerik and Hochstrasser, 2004; D’Andreaand Pellman, 1998; Wilkinson, 1997). Fourof these families are thiol proteases:the ubiquitin-C-terminal hydrolases (UCHs),ubiquitin-specific proteases (USPs),ovarian-tumor (OTU) domain DUBs andMachado-Joseph domain (MJD) DUBs.The DUBs of a fifth family contain aJab1/MPN metalloenzyme (JAMM)domain and act as zinc-dependentmetalloproteases.
The large number of gene families, eachwith multiple members, suggests thatselective pressure to evolve such catalystshas occurred numerous times. In addition,this diversity implies that considerablesubstrate specificity exists. Thisassumption is supported by the finding thatthe mutation, deletion or downregulation
of specific DUBs induces very limitedand specific cellular phenotypes andpathologies (Shanmugham and Ovaa,2008; Singhal et al., 2008). For example,the mutation or deletion of the majorneuronal DUB in mammals, UCH-L1(ubiquitin C-terminal hydrolase L1),causes a localized axonal dystrophy butfew other overt effects (Setsuie and Wada,2007). A benign tumor syndrome of hairfollicles known as cylindromatosis iscaused by the mutation of CYLD, a USP-family DUB named after the disease itcauses. Although the major defects causedby mutation of CYLD are limited to thenuclear factor-κB (NF-κB) pathway,(Courtois, 2008) this DUB has also beenshown to have important roles in cell-cycleregulation (Stegmeier et al., 2007).Interfering with the function of USP1mainly causes DNA-repair defects (Cohnand D’Andrea, 2008), whereas deletingUSP14 in mice results in ataxia, amovement disorder characterized byuncoordinated motions (Crimmins et al.,2006).
A significant aspect of specificity is theability of DUBs to recognize and act ondifferent types of polyubiquitin. Thecatalytic domain of all DUBs contains abinding site for ubiquitin, and severalDUBs bind ubiquitin at submicromolarconcentrations. Many other DUBs,however, bind ubiquitin only very weakly(Reyes-Turcu and Wilkinson, 2009). SomeDUBs have additional binding sites withaffinity for the target protein that isubiquitylated (Ventii and Wilkinson,2008); for example, USP7 binds to apeptide sequence present in its substratesp53, MDM2 (murine double minute 2, anoncoprotein) and the Epstein Barr nuclearantigen-1 (Hu et al., 2006). It is clear thatdifferently linked polyubiquitin chainshave different structures, and it is thoughtthat some DUBs can distinguish betweenthem. For example, the DUBs CYLD andA20, which are involved indownregulating the NF-κB response, onlydisassemble K63-linked polyubiquitinchains, the type that is assembled on thesignaling components of the NF-κBpathway (Courtois, 2008; Heyninck andBeyaert, 2005). Recent structures ofCYLD and A20 suggest that these proteinsachieve specific cleavage of K63-linkedpolyubiquitin chains by recognizing theunique surfaces of ubiquitin that arejuxtaposed in this type of polyubiquitin.Similar conclusions are supported by a
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co-crystal structure containing the JAMMdomain of the DUB AMSH (associatedmolecule with the SH3 domain of STAM)and K63-linked diubiquitin (Sato et al.,2008).
DUBs associate with ubiquitinligases, scaffold proteins andsubstrate adaptorsIn contrast to the specificity of DUBs thatis apparent in vivo, assays carried out usingartificial substrates in vitro often indicatethat DUBs show little specificity. This can,in part, be attributed to the qualitativenature of many assays that do not measurethe rates of substrate cleavage, althoughthis factor alone cannot fully explain theapparent lack of specificity. A more likelyexplanation is that most DUBs containadditional protein interaction domains(which are utilized in vivo but not in invitro) that direct the binding of DUBs tospecific scaffolds or substrate adaptors andthereby confer substrate specificity. Thus,it is thought that in vivo specificity isdetermined mostly by the colocalization ofthe DUB and its substrates, and thatadaptors are necessary for many DUBs tobind to their substrates (Marfany andDenuc, 2008; Ventii and Wilkinson, 2008).For example, USP1 is known to form acomplex with a non-proteolytic subunit,UAF1, and the degradation of UAF1 leadsto proteolysis of USP1 and consequentdefects in the DNA repair functions thatUSP1 is involved in regulating (Cohnand D’Andrea, 2008). Similarly, theproteasome-associated DUBs USP14,UCH37 and POH must all be associatedwith the proteasome for significant DUBactivity (Schmidt et al., 2005; Ventii andWilkinson, 2008).
Another surprising observation is thatseveral DUBs have been found to associatewith ubiquitin ligases, which suggests thatDUBs have a role in regulatingubiquitylation. The proteasome has bothubiquitin ligases and DUBs that associatewith it (Crosas et al., 2006), and severalDUB-ligase pairs interact directly,including BRCC36-BRCA1, BAP1-BRCA1, USP4-Ro52, USP7-MDM2,USP8-GRAIL, USP20-pVHL, USP33-pVHL and USP44-APC (Kee andHuibregtse, 2007; Marfany and Denuc,2008; Ventii and Wilkinson, 2008). Oneexplanation for these associations may bethat the associated DUBs counteract thetendency of ubiquitin ligases toautoubiquitylate in the absence of other
substrates. Another purpose that theinteraction might serve is to targetthe DUB for degradation via the ligase-catalyzed ubiquitylation of the associatedDUB. In at least some cases, the twointeraction partners are indeedtransregulated by each other. For example,in the absence of their substrates, theubiquitin ligases MDM2 and Ro52(Sjogren’s syndrome associatedautoantigen) become autoubiquitylated,and this is reversed by the activity of theirassociated DUBs, USP7 and USP4,respectively (Clegg et al., 2008;Meulmeester et al., 2005; Wada andKamitani, 2006). Conversely, USP4 can beubiquitylated by Ro52 and subsequentlydegraded. However, another function ofthese interactions might be to enforce thesubstrate specificity of ubiquitylation: theaction of the DUB might ‘proofread’ubiquitylation and prevent the assembly ofinappropriate ubiquitin linkages. The DUBA20, which contains both a ligase and aDUB domain on the same polypeptide, isthe most extreme example of this. Itsapparent role is to remodel thepolyubiquitin chains that are generated onRIP1 (receptor-interacting protein 1)during tumor necrosis factor (TNF)-mediated stimulation of the NF-κBpathway. Removing the K63-linkedpolyubiquitin downregulates signaling,and assembling a K48-linked chain onRIP1 drives its degradation, furtherdamping signaling (Heyninck and Beyaert,2005).
Pathological conditions related toDUB dysfunctionDefects in DUB functions have beenimplicated in several pathologicalconditions, most notably cancer,neurological disease and microbialpathogenesis (de Pril et al., 2006;Rytkonen and Holden, 2007; Setsuie andWada, 2007; Shackelford and Pagano, 2005;Singhal et al., 2008; Stuffers et al.,2008; Yang, 2007).
Based on the findings that DUBs have arole in regulating multiple cell-cycle andDNA repair checkpoints, in addition tocytokine-signaling and apoptosispathways, it is likely that defects in DUBfunction could contribute to thedevelopment of cancer. Notably, mutationsin CYLD cause cylindromatosis, and thetranslocation of the UBP6 coding regiondownstream of heterologous promoters isan oncogenic event that is found in
many mesenchymal tumors. Furthermore,deletion of the gene encoding A20 in miceresults in severe inflammation andcachexia (Singhal et al., 2008).
The potential role of DUBs in neurologicaldisease is even less well understood.Mutation of USP14 in mice or ataxin-3 inhumans causes ataxia (Crimmins et al.,2006; Duenas et al., 2006), whereas theS18Y allele of human UCH-L1 confersprotection against sporadic Parkinson’sdisease. UCH-L1 is concentrated in avariety of neuronal inclusion bodies inhumans, and loss-of-function mutationsin this protein cause axonal degeneration inneurons that terminate at the Gracilenucleus, a region of the brainstem thatreceives dorsal-root fibers conveyingsensory innervation of the leg and lowertrunk (Setsuie and Wada, 2007). It ispossible that interfering with DUBfunction leads to cellular stress that is notobvious in most tissues but has a majorimpact in the nervous system, as the deathof a small number of neurons can haveprofound functional consequences.
Finally, it is notable that several bacteria(Rytkonen and Holden, 2007) and viruses(Lindner, 2007) have exploited the host-cell ubiquitin pathway by encoding DUBsthat play a role in infection andpathogenesis. For example, the SARScoronavirus PLpro processing proteaseacts on a broad range of ubiquitylated andISG15-modified host proteins and isrequired for viral replication (Ratia et al.,2008); the obligate intracellular bacterium,Burkholderia mallei, expresses andsecretes a DUB inside infectedmacrophages (Shanks et al., 2009); and theChlaDub1 expressed by Chlamydiatrachomatis suppresses NF-κB activation(Le Negrate et al., 2008). Presumably thesemicrobial DUBs confer a selectiveadvantage on the pathogen bydeubiquitylating host proteins andinterfering with their normal cellularfunctions.
The above examples describe pathologicalconditions that are caused by expression ofheterologous DUBs or by mutationsof endogenous DUBs, although many otherdisease states or cellular functions havebeen shown to be modulated by DUBs.There are only a few DUB mutations thatare currently known to cause disease, but itis very likely that more will be recognizedin the future. It is also probable that other
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DUBs can modulate the effects of disease.Furthermore, as DUB-dependent processesare integral to many regulatory pathways, itis possible that DUBs will prove to beattractive drug targets in cases where thepathological lesions are caused by othermutations or damage events.
PerspectivesIt is apparent that ubiquitin signals arepervasive, flexible and dynamic. Virtuallyevery cellular process that requirestemporally or spatially regulated protein-protein interactions is affected byubiquitylation and deubiquitylation. In thepast three years, numerous DUBs have beenlinked to some of the most vital of cellularfunctions and responses. These enzymescontribute greatly to the dynamic nature ofthe ubiquitin signal, and act by proofreadingand disassembling ubiquitin chains withgreat specificity. This is achieved throughthe specificity of DUBs for their targetproteins, the type of ubiquitin chain thatthey recognize and their cellular location.The associations of DUBs with ubiquitinligases, scaffold proteins, substrates orsubstrate adaptors are also important factorsin conferring this specificity.
The metabolic functions of ubiquitylationand deubiquitylation parallel that ofphosphorylation. There are estimated to be500 or more each of kinases and ubiquitinligases, whereas phosphatases and DUBsnumber around 100 each. Similar to themany kinases and phosphatases that havebeen studied for their therapeutic potential,DUBs have a role in numerousphysiological and pathological processes.Thus it is obvious that opportunitiesabound for pharmacological intervention.As the picture is emerging that each DUBhas a limited set of substrates, the selectiveinterference of an individual DUB mayhave highly selective effects on thelocalization, stability and/or function ofspecific proteins. Therefore, drugs thatinhibit the catalytic activity of specificDUBs, or that interfere with theirinteractions with other proteins, hold greatpromise for modulating the ubiquitin-dependent physiological processes that areinvolved in human disease.
K.D.W. is the recipient of grants GM030308 andGM066355 from the National Institutes of Health.Deposited in PMC for release after 12 months.
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