Ubiquitination, the modification of proteins by the covalent attachment of ubiquitin (Ub), is a key regulatory mechanism for many many cellular processes, including protein degradation by the 26S proteasome. Ub conjugates linked via lysine 48 (K48) target substrates to the proteasome, whereas those linked via any of the six other Ub lysines can alter the function of the modified protein without leading to degradation. Deubiquitination, the reversal of this modification, regulates the function of ubiquitin-conjugated proteins. Deubiquitinating enzymes (DUBs) catalyze the removal of Ub and regulate Ub-mediated pathways.
Given that Ub is covalently-linked to proteins destined to be degraded, it is a surprisingly long-lived protein in vivo (Haas & Bright 1987). This is due to the removal of Ub from its conjugates by DUBs prior to proteolysis. This may represent a quality control mechanism that prevents the degradation of proteins that were inappropriately tagged for degradation (Lam et al. 1997). DUBs are responsible for processing inactive Ub precursors and for keeping the 26S proteasome free of unanchored Ub chains that compete for Ub-binding sites.
DUBs can be grouped into five families based on their conserved catalytic domains (Amerik & Hochstrasser 2004). Four of these families are thiol proteases and comprise the bulk of DUBs, while the fifth family is a small group of Ub specific metalloproteases.
Thiol protease DUBs contain a Cys-His-Asp/Asn catalytic triad in which the Asp/Asn functions to polarize and orient the His, while the His serves as a general acid/base by both priming the catalytic Cys for nucleophilic attack on the (iso)peptide carbonyl carbon and by donating a proton to the lysine epsilon-amino leaving group. The nucleophilic attack of the catalytic Cys on the carbonyl carbon produces a negatively charged transition state that is stabilized by an oxyanion hole composed of hydrogen bond donors. A Cys-carbonyl acyl intermediate ensues and is then hydrolyzed by nucleophilic attack of a water molecule to liberate a protein C-terminal carboxylate and regenerate the enzyme. Ub binding often causes structural rearrangements necessary for catalysis. Many DUBs are inactivated by oxidation of the catalytic cysteine to sulphenic acid (single bond SOH) (Cotto-Rios et al. 2012, Lee et al. 2013). This can be reversed by reduction with DTT or glutathione. The sulphenic acid can be irreversibly oxidized to sulphinic acid (single bond SO2H) or sulphonic acid (single bond SO3H).
Thiol proteases are reversibly inhibited by Ub C-terminal aldehyde, forming a thio-hemiacetal between the aldehyde group and the active site thiol.
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Marzluff WF, Gongidi P, Woods KR, Jin J, Maltais LJ.; ''The human and mouse replication-dependent histone genes.''; PubMedEurope PMCScholia
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Xu G, Tan X, Wang H, Sun W, Shi Y, Burlingame S, Gu X, Cao G, Zhang T, Qin J, Yang J.; ''Ubiquitin-specific peptidase 21 inhibits tumor necrosis factor alpha-induced nuclear factor kappaB activation via binding to and deubiquitinating receptor-interacting protein 1.''; PubMedEurope PMCScholia
Ubiquitin C-terminal hydrolase UCHL5 (UCH37) deubiquitinates TGFBR1, stabilizing TGF-beta receptor complex and prolonging TGF-beta receptor signaling. Deubiqutination of SMAD7 by UCHL5 has not been examined in this context (Wicks et al. 2005). Ubiquitin peptidase USP15 also deubiquitinates and stabilizes TGFBR1, leading to enhanced signaling by TGF-beta receptor complex. USP15 does not affect the ubiquitination status of SMAD7. Amplification of USP15 has recently been reported in glioblastoma, breast and ovarian cancer. In advanced glioblastoma, TGF-beta receptor signaling acts as an oncogenic factor, and USP15-mediated upregulation of TGF-beta receptor signaling may be a key factor in glioblastoma pathogenesis (Eichhorn et al. 2012). The role of UCHL5 was inferred from experiments using recombinant mouse Uchl5 and Smad7 with recombinant human TGF-beta receptors. The role of USP15 was established by experiments using human proteins.
UBP34 (also known as USP34) is a ubiquitin protease that co-precipitates in AXIN-containing complexes. In vitro studies show that the core domain of UBP34 is able to deubiquitinate AXIN purified from HEK293 transfected cells, and knockdown of UBP34 reduces AXIN1 protein levels in vivo. Treatment of UBP34-knockdown cells with the tankyrase inhibitor XAV939 reverses the degradation of AXIN, suggesting that the activity of UBP34 counteracts the tankyrase-dependent ubiquitination and degradation of AXIN. UBP34 plays a not-fully characterized role in the nuclear accumulation of AXIN, where AXIN is thought to positively regulate beta-catenin mediated transcription (Lui et al, 2011).
The C-terminal extension of UCHL5 (UCH37) binds to ADRM1, part of the proteasomal 19S regulatory subunit which is itself a subunit of the 26S proteasome. Binding of UCHL5 enhances its DUB activity (Qiu et al. 2006). UCHL5 forms oligomers in solution that have very low DUB activity. Binding with ADRM1 is 1:1, preventing oligomerization of UCHL5 while making the active site of UCHL5 accessible to Ubiquitin (Jiao et al. 2014). When associated with the proteasome, UCHL5 disassembles poly-Ub chains by hydrolyzing the distal ubiquitin from a chain. This dissassembly of the degradation signal from only the distal end of polyubiquitin chains may selectively rescue poorly ubiquitinated or slowly degraded Ub-protein conjugates from proteolysis (Lam et al. 1997).
ADRM1 (also called Rpn13) interacts with the 26S proteasome base unit PRDM1 (Rpn2) via its amino-terminus and is found in the majority of 26S proteasomes. It is a receptor for Ubiquitin (Ub) that can bind K48-linked di-Ub (Schreiner et al. 2008, Husnjak et al. 2008) and de-ubiquitinating enzymes (DUBs) such as PSMD14 (Rpn11, POH1), USP14, and UCHL5 (UCH37) (Reyes-Turcu et al., 2009). Together, these DUBs disassemble poly-Ub chains and recycle ubiquitin during proteasomal degradation.
Ataxin-3 (ATXN3) is a ubiquitously-expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription.
ATXN3 interacts with RAD23A and RAD23B, multiubiquitin chain receptors involved in modulation of proteasomal degradation. RAD23 binds to Lysine-48-linked (K48) polyubiquitin chains, and with a lower affinity to K63-linked chains, in a length-dependent manner. RAD23 is proposed to bind simultaneously to the 26S proteasome and polyubiquitinated substrates, thereby assisting their delivery to the proteasome (Wang et al. 2000).
The C-terminus of ATXN3 contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the protein to form aggregates that are a hallmark of the neurodegenerative disease spinocerebellar ataxia 3 (SCA3) (Kawaguchi et al. 1994, Evers et al. 2014).
Ataxin-3 (ATXN3) has an N-terminal Josephin domain (JD) that is conserved within a family of around 4 ubiquitin proteases. ATXN3, the best studied, can bind long chains of lysine-63 (K63)-linked and K48-linked poly-ubiquitin (poly-Ub), but its activity is highest for ubiquitin chains with at least four molecules of ubiquitin. It preferentially cleaves linkages between ubiquitin molecules linked through K63 rather than K48 (Winborn et al. 2008). In effect this trims longer polyubiquitin chains down to approximately four residues (Burnett et al. 2003). The other three human JD-containing proteins also have demonstrated deubiquitinase (DUB) activity (Tzvetkov & Breuer 2007). In vitro ATXN3 kinetics are slow when compared to other well-studied deubiquitinating enzymes (Nicastro et al. 2010) but become much faster when ATXN3 is activated by VCP (Laco et al. 2012). JOSD1 partially localizes to the plasma membrane (Seki et al. 2013).
Ataxin-3 (ATXN3) binds Valosin-containing protein (VCP) (Dos-Pepe et al. 2003), a 26S proteasome-associated multiubiquitin chain-targeting factor required for protein degradation by the ubiquitin-proteasome pathway (Dai & Li 2001). One of the functions of VCP is the regulation of misfolded endoplasmic reticulum (ER) proteins a process named ER-associated degradation (ERAD) (Zhong & Pittman 2006, Liu & Ye 2012). VCP increases the ubiquitinase activity of ATXN3 (Laco et al. 2012) and may act as an 'uncoupling factor' that transfers ubiquitinated substrates from RAD23 to ATXN3 (Doss-Pepe et al. 2003). In this model multiubiquitinated proteolytic substrates bind to RAD23 through its UBA domains, while VCP associates with ATXN3 at the proteasome. RAD23 plus substrate would bind to the proteasome (conceivably an ataxin-3-containing proteasome) via its UbL domain. VCP would transfer multiubiquitinated substrates from RAD23 to ATXN3 (Doss-Pepe et al. 2003). VCP is found as a component of abnormal protein aggregates (Hirabayashi et al. 2001) and has been identified as a modulator of polyglutamine-induced neurodegeneration (Higashiyama et al. 2002). Mutant ATXN3 with an expanded polyQ tract binds VCP more efficiently than wild-type ATXN3, interfering with the degradation of ubiquitinated substrates (Laco et al. 2012).
Ataxin-3 (ATXN3) deubiquitinates the C-terminus of PARK2 (Parkin) (Winborn et al. 2008, Durcan et al. 2011). This promotes the degradation of PARK2.
An unstable CAG trinucleotide repeat expansion in the ATXN3 gene leads to elongation of the polyglutamine (polyQ) tract within the ATXN3 protein, and is believed to be the cause of Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited form of ataxia (Martins et al. 2007). Both wild-type and polyQ-expanded ATXN3 can deubiquitinate PARK2, regardless of the lysine residue used to assemble poly-Ub chains. The polyQ-expanded ATXN3 deubiquitinates PARK2 more efficiently than wild-type ATXN3, but the mutant rather than the wild-type ATXN3 promoted the clearance of PARK2 via the autophagy pathway. This apparent contradiction may be due to increased removal of K27- and K29-linked Ub conjugates on PARK2 by the polyQ-expanded ATXN3; Ub conjugates linked in this manner to PARK2 may protect it from autophagic degradation (Durcan et al. 2011).
Ubiquitin conjugates linked via lysine-48 (K48) target substrates to the proteasome, whereas those linked via any of the six other ubiquitin lysines can alter the function of the modified protein without leading to degradation. Parkin (PARK2) was found to autoubiquitinate itself predominantly via K6, K27, K29 and K63-linked ubiquitination, rather than via K48 (Durcan et al. 2011).
ADRM1 (Rpn13) interacts with the 26S proteasome base unit PRDM1 (Rpn2) via its amino-terminus and is found in the majority of 26S proteasomes. ADRM1 can bind K48-linked di-Ubiquitin (Schreiner et al. 2008, Husnjak et al. 2008) and several de-ubiquitinating enzymes (DUBs) including PSDM14 (Rpn11, POH1), part of the 26S proteasome, and USP14 (Borodovsky et al. 2001, Reyes-Turcu et al. 2009). These proteasome-associated DUBs disassemble poly-Ub chains and recycle ubiquitin during proteasomal degradation. They may also act to prevent the degradation of mis-tagged proteins.
BRCA1-associated protein 1 (BAP1) is a ubiquitin COOH-terminal hydrolase that was initially identified as a protein that binds the RING finger domain of the breast and ovarian tumor suppressor BRCA1. BAP1 is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway (Murali et al. 2013).
The C-terminal coiled coil motif of BAP1 directly interacts with the zinc fingers of the transcription factor Yin Yang 1 (YY1) (Yu et al. 2010), part of a multiprotein complex containing numerous transcription factors and cofactors including the transcriptional regulator Host cell factor 1 (HCFC1), which binds the N-terminal portion of BAP1 (Misaghi et al. 2009, Machida et al. 2009). HCFC1 is a chromatin-associated protein initially identified as part of a multiprotein complex comprising the viral coactivator VP16 and the POU domain transcription factor POU2F1. During herpes simplex virus infection, this complex is recruited to the enhancer/promoter of the immediate-early gene to activate viral gene expression (Kristie et al. 2010).
The C-terminal extension of UCHL5 mediates association with Adrm1/Rpn13 of the proteasomal 19S regulatory subunit and with NFRKB of the INO80 chromatin remodeling complex. The extreme C-terminal segment of BAP1 is 38% identical to the C-terminus of UCHL5 (UCH37) and is necessary for binding to YY1 (Yu et al. 2010).
BRCA1-associated protein 1 (BAP1) is a ubiquitin COOH-terminal hydrolase that was initially identified as a protein that binds the RING finger domain of the breast and ovarian tumor suppressor BRCA1. The extreme C-terminal segment of BAP1, which is 38% identical to the C-terminus of UCHL5 (UCH37), is necessary for binding to BRCA1 (Jensen et al. 1998). The N-terminal portion of BAP1 binds BARD1 (Nishikawa et al. 2009). BARD1:BRCA1 constitutes a RING heterodimer E3 ligase. BAP1 binding with BARD1 interferes with BARD1-BRCA association. BAP1 can also deubiquitinate the polyubiquitin chains mediated by BRCA1:BARD1 (Nishikawa et al. 2009).
BAP1 is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway (Murali et al. 2013).
USP7 (HAUSP) is able to deubiquitinate many substrates. It is a key regulator of the tumor suppressor TP53 (p53) (Vousden & Lu 2002). It can act on TP53 directly, or indirectly by acting on the E3 ligase MDM2, which can ubiquitinate TP53 (Chene 2003, Li et al. 2002, 2004, Kon et al. 2010). USP7 also regulates MDM4 (Mdmx), a structural homolog of MDM2 (Meulmeester et al. 2005, Chen 2012). USP7 interacts with and deubiquitinates FOXO4 in response to oxidative stress (van der Horst et al. 2006) and reduces monoubiquitinylation of PTEN, presumably on the previously identified lysine residues 13 and 289 (Trotman et al. 2007), reducing nuclear PTEN levels (Song et al. 2008).
USP10 specifically deubiquitinate p53 and not MDM2 (Yuan et al. 2010). USP24 and USP42 also can deubiquitinate p53, regulating the DNA damage response following UV-damage (Hock et al. 2011, Zhang et al. 2015).
USP3 dynamically associates with chromatin and deubiquitinates H2A and H2B in vivo. The ZnF-UBP domain of USP3 mediates the H2A-USP3 interaction (Nicassio et al. 2007). USP22, a component of the hSAGA transcriptional coactivator complex, is able to deubiquitinate Histone H2A and H2B (Zhang et al. 2008, Zhao et al. 2008).
USP5 (Isopeptidease T) cleaves linear and branched polyubiquitin (polyUb) with a preference for branched polymers (Wilkonson et al. 1995). It is Involved in the disassembly of unattached lysine-48-linked (K48) polyUb. It also binds linear and K63-linked polyUb with a lower affinity (Dayal et al. 2009).
USP21 is not required for normal development (Pannu et al. 2015) but is essential in innate and adaptive immune responses (Tao et al. 2014). It negatively regulates NFkB signaling by deubiquitinating Receptor-interacting protein 1 (RIPK1) (Xu et al. 2010) and DDX58 (RIG-I), thereby down-regulating antiviral responses independently of the A20 ubiquitin-editing complex (Fan et al. 2014).
The ubiquitin E3 ligase RNF128 (GRAIL) is regulated by auto-K48-linked ubiquitination, which leads to its proteasomal degradation. RNF128 is bound but not deubiquitinated by OTUB1. USP8 binds the RNF128:OTUB1 complex to remove the ubiquitin attached to GRAIL (Soares et al. 2004, Whiting et al. 2011).
UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers (Wilkinson et al. 1989, Wada et al. 1998, Larsen et al. 1998). This liberates small molecule nucleophiles that may have inadvertently reacted with Ub C-terminal thiolesters. Because these enzymes can cleave small peptides from the C-terminus of Ub, they could also function in recycling Ub from incomplete proteasomal or lysosomal protein degradation. UCHL3, but not UCHL1, is able to cleave the C-terminus of Neural precursor cell expressed developmentally downregulated protein 8 (NEDD8), a ubiquitin-like protein that activates the largest ubiquitin E3 ligase family, the cullin-RING ligases (Wada et al. 1998, Enchev et al. 2015). UCHL1 and 3 are specifically expressed in neurons, cells of the diffuse neuroendocrine system and their tumors. A polymorphism (S18Y) in UCHL1 is associated with a reduced risk for Parkinson's disease (Wang et al. 2002) and its overexpression is protective in models of Alzheimer's disease (Gong et al. 2006). UCHL1 has been shown to interact with alpha-synuclein, but as a ubiquitin ligase rather than as a ubiquitin hydrolase (Liu et al. 2002). It is K63-polyubiquitinated by Parkin in cooperation with the Ubc13/Uev1a E2 ubiquitin-conjugating enzyme complex, promoting UCH-L1 degradation by the autophagy-lysosome pathway (McKeon et al. 2015).
BRCA1 associated protein 1 (BAP1) is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway (Murali et al. 2013). BAP1 mediates the deubiquitination of Host cell factor 1 (HCFC1) thereby regulating cell growth (Eletr & Wilinson 2011), though deubiquitination of HCFC1 does not lead to increased HCFC1 stability. HCFC1 is K48 and K63 ubiquitinated; the major site of linkage are lysines 1807 and 1808 (Machida et al. 2009).
BRCA1 associated protein 1 (BAP1) is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway (Eletr & Wilkinson 2011, Murali et al. 2013). BAP1 mediates the deubiquitination of Host cell factor 1 (HCFC1) thereby regulating cell growth, though deubiquitination of HCFC1 does not lead to increased HCFC1 stability. HCFC1 is K48 and K63 ubiquitinated. The major site of linkage are lysines 1807 and 1808 (Machida et al. 2009).
BAP1 is the catalytic component of the PR-DUB complex, which deubiquitinates Lysine-120 monoubiquitinated Histone H2A (H2AK119ub1) (Scheuermann et al. 2010). The PR-DUB complex consists of BAP1, ASXL1/2, KDM1B, FOXK1/2, HCFC1 and MBD5/6 (Yu et al. 2010, Dey et al. 2012, Baymaz et al. 2014).
UCHL3 and SENP8 (DEN1) remove the C-terminal extension of NEDD8 propeptides, exposing a C-terminal Gly residue. UCHL3 can also process ubiquitin (Wada et al. 1998). UCHL3 and SENP8 are probably functionally redundant in NEDD8 processing as deletion of either enzyme does not lead to neddylation defects (Chan et al. 2008, Kurihara et al. 2000).
The carboxy-terminal domain of TNFAIP3 (A20) functions as a ubiquitin ligase, polyubiquitinating RIPK1 with K48-linked ubiquitin chains, thereby targeting it for proteasomal degradation (Wertz et al. 2004).
OTUB1 (and OTUB2) can bind TP53 ( Sun et al. 2012) RNF128 (GRAIL) (Soares et al. 2009), TRAF3 and TRAF6 (Li et al. 2010) and RhoA (Edelmann et al. 2010). OTUB1 has DUB activity but mainly acts by suppressing ubiquitin-conjugating E2 enzymes, independently of its catalytic activity (Sun & Dai 2014).
TNFAIP3-interacting protein (TNIPs), also known as A20-binding inhibitors of NF-kappa-B activation (ABINs), bind TNFAIP3, the ubiquitin-editing nuclear factor-kappaB (NF-kappaB) inhibitor protein A20 (Heyninck et al. 1999). Overexpression of TNIPs inhibits NF-kappaB activation by tumor necrosis factor (TNF). TNIPs have a ubiquitin-binding domain that is essential for their NF-kappaB inhibitory and anti-apoptotic activities. They may function as adaptors between ubiquitinated proteins and other regulatory proteins, or disrupt signaling complexes by competing with other ubiquitin-binding proteins (Verstrepen et al. 2009).
TNFAIP3 (A20) removes lysine-63 (K63)-linked ubiquitin chains from Receptor interacting protein (RIPK1), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20 then functions as a ubiquitin ligase, polyubiquitinating RIPK1 with K48-linked ubiquitin chains, thereby targeting RIPK1 for proteasomal degradation (Wertz et al. 2004) which leads to termination of TNF- or LPS-mediated activation of NF-kappa-B.
OTUD7D (Cezanne) negatively regulates the non-canonical NFkappaB pathway by removing Lys-48-linked polyubiquitin chains from TRAF6, preventing TRAF6 proteolysis, which causes over-activation of non-canonical NFkappaB and negative regulation of B-cell responses (Evans et al. 2001).
TNFAIP3 has the opposite effect, it can remove K63-linked ubiquitin from TRAF6, which terminates signalling by Toll-like receptors (Boone et al. 2004). TNFAIP3 is essential for the termination of NFkappaB activation in response to multiple stimuli such as IL-1beta, TNF, IL-6, CD40 and lipopolysaccharide (LPS) (Vereecke et al. 2009).
MYSM1 is required for full activation of several transcriptional events, including androgen receptor (AR)-regulated target genes in prostate cancer cells. It is part of a regulatory protein complex with the histone acetyltransferase EP300 (p300) and KAT2B (CBP-associated factor (p/CAF)), regulating transcriptional initiation and elongaion by coordinating histone acetylation, H2A deubiquitination and linker histone dissociation. MYSM1 preferentially deubiquitinates H2A in hyperacetylated nucleosomes (Zhu et al. 2007).
BRCC3 (BRCC36) as part of the BRCA1-A complex, antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks (Shao et al. 2009), specifically removing Lysine-63-linked polyubiquitin on histone H2A and H2AX. K63-linked polyubiquitination of H2A is induced by DNA damage and is required for the DNA repair response (Cao & Yan, 2012).
PSMD14 (RPN11, POH1) is a subunit of the proteasomal 19S lid complex that specifically cleaves Lysine-63-linked polyubiquitin chains (Yao & Cohen 2002, Butler et al. 2012).
As part of the cytosolic BRISC complex (Cooper et al. 2009), BRCC3 regulates NLRP3 activity by promoting K63-deubiquitination of its LRR domain (Py et al. 2013). The consequent activation of NLRP3 has been proposed to mediate necrotic cell sensing and the subsequent release of the proinflammatory cytokine IL-1Beta after hypoxic injury (Iyer et al. 2009).
STAMBP (AMSH) was identified as an interacting partner of the SH3 domain of STAM (Tanaka et al. 1999) and later characterized as a Zn2+-dependent ubiquitin isopeptidase with a substrate preference for Lys-63-linked polyubiquitin chains (McCullough et al. 2004, 2006).
At the N terminus STAMBP contains a nuclear localization signal and a microtubule-interacting and transport (MIT) domain that can interact with several chromatin-modifying proteins that are components of the Endosomal sorting complex required for transport (ESCRT) III complex (Sierra et al. 2010). STAMBP binds clathrin heavy chains, which anchors it to endosomes (McCullough et al. 2006, Nakamura et al. 2006) and contains a STAM-interacting motif that binds the SH3 domain of STAM, stimulating the deubiquitinating activity of STAMBP (McCullough et al. 2006, Kim et al. 2006, Sierra et al. 2010).
Ubiquitination plays a key role in the regulation of signaling via TAK1 (Chen 2012). USP18 catalyzes the deubiquitination of the TAK1:TAB1 complex, reversing TAK1 activating ubiquitination, which restricts activation of NF-kappaB, NFAT and JNK and in decreases the expression of IL2 in T cells after TCR activation (Liu et al. 2013).
STAMBPL1 (AMSH-LP) has Lys-63 deubiquitinase activity (Sato et al. 2008) and positively regulates TGF-beta signaling (Ibarolla et al. 2004) but unlike STAMBP (AMSH1) it does not bind STAM (Kikuchi et al. 2003).
USP25, a negative regulator of the virus-triggered type I IFN signaling pathway, cleaves lysine 48- and lysine 63-linked polyubiquitin chains in vitro and in vivo from DDX58 (Retinoic acid-inducible gene I (RIG-I)), Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and TRAF6 to inhibit RIG-I-like receptor-mediated IFN signaling (Zhong et al. 2013).
USP17 regulates cell proliferation by deubiquitinating and inhibiting RCE1, which influences the localization and activation of the small GTPases NRAS and HRAS (Burrows et al. 2009). In addition, USP17 mediates deubiquitination of CDC25A, which prevents CDC25A degradation by the proteasome during the G1/S and G2/M phases, promoting cell-cycle progression (Pereq et al. 2010). USP17 cleaves Lys-48 and Lys-63-linked polyubiquitin chains from the cytoplasmic innate immune receptors DDX58 (RIG-I) and IFIH1 (MDA5), which increases activation of the IFN-beta promoter, part of the cellular response to viral infection (Chen et al. 2010). USP17 expression is upregulated by interleukin-4 and interleukin-6 (Burrows et al. 2004).
USP12 (as part of a complex with WDR48 and WDR20) and USP26 can bind the androgen receptor and promote its deubiquitination (Faus et al. 2005, Burska et al. 2013, Dirac & Bernards 2010). USP26 is specifically expressed in testis tissue and is a potential infertility gene (Stouffs et al. 2005).
CYLD removes Lys63-linked ubiquitin chains, acting as a negative regulator of NF-kappa-B signaling (Trompouki et al. 2003). It deubiquitinates several NF-kappa-B regulators including TRAF2, TRAF6 (Kovalenko et al. 2003, Trompouki et al. 2003), IKBKG (NEMO) (Brummelkamp et al. 2003), and RIPK1 (Wright et al. 2007).
USP30 is a deubiquitinating enzyme that associates with the mitochondrial outer membrane. RNAi depletion of USP30 induces elongated, interconnected mitochondria, suggesting that USP30 contributes to mitochondrial morphology (Nakamura & Hirose 2008).
Overexpression of USP30 removes ubiquitin attached to damaged mitochondria by PARK2 (Parkin), preventing PARK2-induced mitophagy, whereas reducing USP30 enhances mitochondrial degradation in neurons. Multiple mitochondrial substrates were found to be oppositely regulated by PARK2 and USP30. Knockdown of USP30 rescues defective mitophagy caused by pathogenic mutations in parkin and improves mitochondrial integrity in parkin- or Pink1-deficient flies. Knockdown of Usp30 in dopaminergic neurons protects flies against paraquat toxicity in vivo, ameliorating defects in dopamine levels, motor function, and organismal survival (Bingol et al. 2014).
USP28 is Involved in DNA damage induced apoptosis by specifically stabilizing and deubiquitinating proteins of the DNA damage pathway including CLSPN (Zhang et al. 2006). It also binds to the nucleoplasmic alpha isoform of Fbw7, counteracting FBW7 ubiquitin ligase activity by deubiquitinating MYC in the nucleoplasm, which reduces MYC proteasomal degradation (Popov et al. 2007).
USP33 regulates centrosome duplication by mediating deubiquitination and stabilization of CCP110 in S and G2/M phase (Li et al. 2013) and regulates G-protein coupled receptor (GPCR) signaling by deubiquitinating beta-arrestins (ARRB1 and ARRB2) (Shenoy et al. 2009).
USP47 specifically deubiquitinates monoubiquitinated DNA polymerase beta (POLB), increasing its stability and thereby playing a role in base-excision repair (Parsons et al. 2011).
USP44 specifically mediates the deubiquitination of CDC20, which promotes the association of MAD2L1 and CDC20, which in turn increases the stabilty of the MAD2L1-CDC20-APC/C ternary complex (Mitotic Checkpoint Complex), thereby preventing premature activation of the Anaphase Promoting Complex/Cyclosome (APC/C) (Stegmeier et al. 2007).
USP20 and USP33 act as a regulators of G-protein coupled receptor (GPCR) signaling by mediating the deubiquitination of the beta-2 adrenergic receptor (ADRB2), prolonging agonist stimulation and inhibiting lysosomal trafficking (Berthouze et al. 2009).
USP37 deubiquitinates Lys-11-linked polyubiquitin chains from cyclin-A (CCNA1 and CCNA2), which opposes the Lys-11-linked polyubiquitination mediated by the anaphase-promoting complex (APC/C) during G1/S transition, thereby promoting S phase entry. Phosphorylation by CDK2 at Ser-628 during G1/S phase maximizes USP37 deubiquitinase activity (Huang et al. 2011).
USP15 is a ubiquitin-specific protease (Baker et al. 1999) reported to act on several substrates. It promotes deubiquitination of monoubiquitinated R-SMADs, indirectly promoting the activation of TGF-beta target genes (Inui et al. 2011). USP15 binds the SMAD7:SMURF2 complex, deubiquitinating and stabilizing the type I TGFBeta receptor (TGFBR1), leading to enhanced TGF-Beta signalling (Eichorn et al. 2012). USP15 deubiquitinates KEAP1, which suppresses the Nrf2 pathway (Villeneuve et al. 2013).
USP13 preferentially cleaves Lys-63-linked polyubiquitin chains (Zhang et al. 2011). It mediates deubiquitination of BECN1, a key regulator of autophagy, which stabilizes PIK3C3/VPS34-containing complexes. USP13 can deubiquitinate USP10, an essential regulator of TP53 stability (Liu et al. 2011).
USP19 promotes the stability of BIRC2 (c-IAP1) and BIRC3 (c-IAP2) by preventing them from self-ubiquitinating (Mei et al. 2011). Similarly, USP19 promotes the stability of the hypoxia-inducible factor 1-alpha (HIF-1a), with a mechanism that is independent of its catalytic activity (Altun et al. 2012).
USP19 is a deubiquitinating enzyme with a preference towards Lys-63-linked ubiquitin chains (Iphofer et al. 2012). It deubiquitinates RNF123, preventing its proteasomal degradation which in turn stimulates CDKN1B ubiquitin-dependent degradation and thereby cell proliferation (Lu et al. 2009).
USP13 mediates stabilization of the E3-ligase SIAH2 independently of deubiquitinase activity by binding and impairing SIAH2 autoubiquitination (Scortegagna et al. 2011).
ZRANB1 (Trabid) binds and cleaves K63-linked ubiquitin chains. It is required for efficient TCF-mediated transcription in cells with high Wnt pathway activity, including colorectal cancer cell lines. ZRANB1 can deubiquitinate the APC tumor suppressor protein, a negative regulator of Wnt-mediated transcription (Tran et al. 2008).
In the nucleus USP13 binds UFD1 which acts as a scaffold connecting USP13 to SKP2. USP13 mediates the deubiquitination of SKP2, thereby regulating endoplasmic reticulum-associated degradation (ERAD) by counteracting APC/C(Cdh1)-mediated SKP2 ubiquitination (Chen et al. 2011).
YOD1 (OTU1) is a highly conserved deubiquitinating enzyme of the ovarian tumor (otubain) family. It forms a complex with Valosin containing protein (VCP, p97) that may participate in endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins (Ernst et al. 2009, Kim et al. 2014). It may act by triming the ubiquitin chain on the associated substrate to facilitate their threading through the VCP/p97 pore. Ubiquitin moieties on substrates may present a steric impediment to the threading process when the substrate is transferred to the VCP pore and threaded through VCP's axial channel.
USP10 deubiquitinates and stabilizes endogenous SNX3 and consequently promotes cell surface expression of ENaC (Boulkroun et al. 2008). USP10 deubiquitinates CFTR in early endosomes thereby enhancing its endocytic recycling (Bomberger et al. 2009).
Monoubiquitination of cell surface receptors is a sorting signal that leads to receptor trafficking from endosomes to lysosomes. Ubiquitinated protein sorting is carried out by class E vacuolar protein sorting (Vps) proteins. Some of these proteins are regulated by monoubiquitination. The Hrs-STAM complex, which is essential for the initial step of the sorting pathway, binds the deubiquitinating enzymes USP8 (UBPY) and STAMBP (AMSH). These bind STAM2 at the same site and may compete for binding (Kato et al. 2000). STAM2 stability is dramatically reduced in USP8 knockdown cells suggesting that its degradation is reduced by the DUB action of USP8 (Row et al. 2006).
USP17 removes Lys-63-linked ubiquitin chains from SDS3, a key component of the histone deacetylase (HDAC)-dependent Sin3A co-repressor complex, serving to maintain its HDAC activity (Ramakrishna et al. 2011).
Though not required for normal development (Pannu et al. 2015), USP21 is essential in innate and adaptive immune responses (Tao et al. 2014). It deubiquitinates the Th2 specific transcription factor GATA3. This positive regulation is important for the function of regulatory T cells (Zhang et al. 2013). USP21 also deubiquitinates IL-33, which is both a cytokine and a chromatin-associated nuclear protein known as Nuclear factor from high endothelial venule (NF-HEV), which is associated with many inflammatory diseases (Garlanda et al. 2013). IL-33 can bind to the RELA (NFkB p65) promoter region, inducing endothelial cell activation (Choi et al. 2012). Depletion of USP21 reduces IL-33 protein levels and IL-33-mediated RELA promoter activity (Tao et al. 2014).
OTUB1 (and OTUB2) can bind the nuclear proteins MDM2 cognate E2 UBE2D1 (Sun et al. 2012), and ESR1 (Stanisic et al. 2009). OTUB1 has DUB activity but mainly acts by suppressing ubiquitin-conjugating E2 enzymes, independently of its catalytic activity (Sun & Dai 2014).
The deubiquitinase A20 is a negative feedback regulator of inflammatory responses, induced by NFkappaB activation (Krikos et al. 1992) and NOD stimulation (Masumoto et al. 2006). A20 can deubiquitinate RIP2 and restricts NOD2 induced signals (Hitosumatsu et al. 2008).
USP48 (confusingly referred to as USP31 in some literature) is a deubiquitinating enzyme that cleaves preferentially lysine-63-linked polyubiquitin chains. USP48 can also cleave lysine-48-linked polyubiquitin chains albeit to a lesser extent. USP48 can interact with TRAF2, and overexpression of USP48 inhibits NF-?B activation suggesting that it may remove ubiquitin from TRAF2, TRAF6 or another essential intermediate that lies downstream of TRAFs.
OTU domain-containing protein 7A (CEZANNE2, OTUD7A ) has deubiquitinating activity that is specific for Lys11 ubiquitin linkages (Mevissen et al 2013).
USP4 specifically interacts with tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and TRAF6 but not TRAF3. It deubiquitinates both TRAF2 and TRAF6 in vivo and in vitro, negatively regulating TNFalpha and IL-1beta-induced NF-kappaB activation and cancer cell migration (Xiao et al. 2012). USP25, a negative regulator of the virus-triggered type I IFN signaling pathway, cleaves lysine 48- and lysine 63-linked polyubiquitin chains in vitro and in vivo from DDX58 (Retinoic acid-inducible gene I (RIG-I)), TRAF2, and TRAF6 to inhibit RIG-I-like receptor-mediated IFN signaling (Zhong et al. 2013).
TNFAIP3 can remove K63-linked ubiquitin from TRAF6, which terminates signalling by Toll-like receptors (Boone et al. 2004). TNFAIP3 is essential for the termination of NFkappaB activation in response to multiple stimuli such as IL-1beta, TNF, IL-6, CD40 and lipopolysaccharide (LPS). Removal of K63-linked ubiquitin is not necessarily followed by K48-ubiquitination that would lead to degradation (Vereecke et al. 2009).
OTUD3 de-polyubiquitylates and stabilizes PTEN, effectively removing Lys 48-linked polyubiquitylation, but not monoubiquitylation nor the non-degradative Lys 63-linked polyubiquitylation of PTEN. In vitro OTUD3 efficiently removed the Lys 6, Lys 11, Lys 27 and Lys 48 types of ubiquitin chain on PTEN (Yuan et al. 2015).
Valosin-containing protein p97/p47 complex-interacting protein 1 (VCPIP1, VCIP135) enzymatic activity is required for p97/p47 (VCP/NSFL1C) -mediated Golgi membrane fusion (Wang et al. 2004). In vitro it displays highest activity toward K11- and K48-linked ubiquitin chains (Mevissen et al. 2013, Zhang & Wang 2015).
VCPIP1 is highly phosphorylated in mitosis. This reduces its association with Golgi membranes and its interaction with VCP and is thought to regulate VCP function in the fusion of the postmitotic Golgi membrane (Zhang et al. 2014).
The N-terminal half of VCPIP1 has a single phosphorylation site, S131 (Zhang et al. 2014). A S131A mutant (serine mutated to alanine) exhibited strong DUB activity, while a phosphomimetic S131E (serine mutated to glutamic acid) mutant had no detectable activity suggesting that S131 phosphorylation regulates VCPIP1 DUB activity. Phosphorylation of VCPIP1 by CDK1 at S131 was sufficient to inactivate the enzyme and inhibit p97/p47-mediated Golgi membrane fusion. Dephosphorylation of VCPIP1 with the CDK1 inhibitor roscovitine significantly increased the DUB activity of endogenous VCPIP1 and attenuated p97/p47-mediated Golgi membrane fusion (Zhang & Wang 2015).
OTUD5 (Deubiquitinating enzyme A (DUBA)) is a negative regulator of type I interferon (IFN-) production. TRAF3, an E3 ubiquitin ligase that preferentially assembles lysine-63-linked polyubiquitin chains, is one of the targets of OTUD5. Expression of DUBA increases the cleavage of K63-linked ubiquitin chains from TRAF3, resulting in its dissociation from the downstream signaling complex that contains TANK-binding kinase 1 (TBK1) (Kayagaki et al. 2007), which leads to blockade of IRF3 and IRF7 phosphorylation.
CYLD is an ovarian tumor (OTU) domain-containing deubiquitinating enzyme (DUB) and has been identified as a negative regulator of DDX58 (RIG-I) mediated antiviral signaling. CYLD associates with the CARD domain of DDX58 and removes K63-linked ubiquitin from the DDX58 CARDs that are conjugated by the E3 ubiquitin ligase, TRIM25 and RNF135.
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PolyUb-CDC25A, PolyUb-DDX58,
PolyUb-IFIH1dsRNA:IFIH1, viral
dsRNA:K63polyUb-DDX58:MAVS:K63polyUb-TRAF3dsRNA:IFIH1, viral
dsRNA:K63polyUb-DDX58:MAVS:TRAF3Annotated Interactions
ATXN3 interacts with RAD23A and RAD23B, multiubiquitin chain receptors involved in modulation of proteasomal degradation. RAD23 binds to Lysine-48-linked (K48) polyubiquitin chains, and with a lower affinity to K63-linked chains, in a length-dependent manner. RAD23 is proposed to bind simultaneously to the 26S proteasome and polyubiquitinated substrates, thereby assisting their delivery to the proteasome (Wang et al. 2000).
The C-terminus of ATXN3 contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the protein to form aggregates that are a hallmark of the neurodegenerative disease spinocerebellar ataxia 3 (SCA3) (Kawaguchi et al. 1994, Evers et al. 2014).
An unstable CAG trinucleotide repeat expansion in the ATXN3 gene leads to elongation of the polyglutamine (polyQ) tract within the ATXN3 protein, and is believed to be the cause of Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited form of ataxia (Martins et al. 2007). Both wild-type and polyQ-expanded ATXN3 can deubiquitinate PARK2, regardless of the lysine residue used to assemble poly-Ub chains. The polyQ-expanded ATXN3 deubiquitinates PARK2 more efficiently than wild-type ATXN3, but the mutant rather than the wild-type ATXN3 promoted the clearance of PARK2 via the autophagy pathway. This apparent contradiction may be due to increased removal of K27- and K29-linked Ub conjugates on PARK2 by the polyQ-expanded ATXN3; Ub conjugates linked in this manner to PARK2 may protect it from autophagic degradation (Durcan et al. 2011).
The C-terminal coiled coil motif of BAP1 directly interacts with the zinc fingers of the transcription factor Yin Yang 1 (YY1) (Yu et al. 2010), part of a multiprotein complex containing numerous transcription factors and cofactors including the transcriptional regulator Host cell factor 1 (HCFC1), which binds the N-terminal portion of BAP1 (Misaghi et al. 2009, Machida et al. 2009). HCFC1 is a chromatin-associated protein initially identified as part of a multiprotein complex comprising the viral coactivator VP16 and the POU domain transcription factor POU2F1. During herpes simplex virus infection, this complex is recruited to the enhancer/promoter of the immediate-early gene to activate viral gene expression (Kristie et al. 2010).
The C-terminal extension of UCHL5 mediates association with Adrm1/Rpn13 of the proteasomal 19S regulatory subunit and with NFRKB of the INO80 chromatin remodeling complex. The extreme C-terminal segment of BAP1 is 38% identical to the C-terminus of UCHL5 (UCH37) and is necessary for binding to YY1 (Yu et al. 2010).
BAP1 is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway (Murali et al. 2013).
TNFAIP3 has the opposite effect, it can remove K63-linked ubiquitin from TRAF6, which terminates signalling by Toll-like receptors (Boone et al. 2004). TNFAIP3 is essential for the termination of NFkappaB activation in response to multiple stimuli such as IL-1beta, TNF, IL-6, CD40 and lipopolysaccharide (LPS) (Vereecke et al. 2009).
VCPIP1 is highly phosphorylated in mitosis. This reduces its association with Golgi membranes and its interaction with VCP and is thought to regulate VCP function in the fusion of the postmitotic Golgi membrane (Zhang et al. 2014).
The N-terminal half of VCPIP1 has a single phosphorylation site, S131 (Zhang et al. 2014). A S131A mutant (serine mutated to alanine) exhibited strong DUB activity, while a phosphomimetic S131E (serine mutated to glutamic acid) mutant had no detectable activity suggesting that S131 phosphorylation regulates VCPIP1 DUB activity. Phosphorylation of VCPIP1 by CDK1 at S131 was sufficient to inactivate the enzyme and inhibit p97/p47-mediated Golgi membrane fusion. Dephosphorylation of VCPIP1 with the CDK1 inhibitor roscovitine significantly increased the DUB activity of endogenous VCPIP1 and attenuated p97/p47-mediated Golgi membrane fusion (Zhang & Wang 2015).
PolyUb-CDC25A, PolyUb-DDX58,
PolyUb-IFIH1PolyUb-CDC25A, PolyUb-DDX58,
PolyUb-IFIH1dsRNA:IFIH1, viral
dsRNA:K63polyUb-DDX58:MAVS:K63polyUb-TRAF3dsRNA:IFIH1, viral
dsRNA:K63polyUb-DDX58:MAVS:TRAF3