去泛素化酶活性的调控
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摘要
泛素化是一种非常重要的蛋白质翻译后修饰方式,在细胞生命活动的各个方面发挥作用。泛素化修饰是可逆的过程,去泛素化酶通过催化去除底物蛋白质上的泛素从而逆转该过程。去泛素化酶是一类数量众多的蛋白水解酶家族,近年来不断有新的去泛素化酶被发现和报道。鉴于其在细胞功能中的重要作用,去泛素化酶活性受到严格的调控。目前的研究表明,影响去泛素化酶活性的因素很多。本文主要从转录水平的调控、翻译后修饰、蛋白质定位和蛋白质相互作用等调控方式进行论述,以期为研究和利用去泛素化酶治疗疾病提供新思路。
Ubiquitylation is a post-translational modification that plays key roles in various biological processes. It is reversely catalyzed by deubiquitinating enzymes(DUBs),which cleave ubiquitin from substrate proteins. DUBs constitute a diverse protein family that play critical roles in cellular functions.The activity of DUBs are tightly and intricately regulated by four major regulatory mechanisms: regulation of gene expression, post-translational modifications, protein-protein interaction and subcellular localization. Here we review the progresses in this field,and hope to provide strategies to target DUBs for therapeutic purposes.
Ubiquitylation is a post-translational modification that plays key roles in various biological processes. It is reversely catalyzed by deubiquitinating enzymes(DUBs),which cleave ubiquitin from substrate proteins. DUBs constitute a diverse protein family that play critical roles in cellular functions.The activity of DUBs are tightly and intricately regulated by four major regulatory mechanisms: regulation of gene expression, post-translational modifications, protein-protein interaction and subcellular localization. Here we review the progresses in this field,and hope to provide strategies to target DUBs for therapeutic purposes.
引文
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[3]Wei R,Liu X,Yu W,et al.Deubiquitinases in cancer[J].Oncotarget,2015,6(15):12872-12889
[4]Mevissen TET,Komander D.Mechanisms of deubiquitinase specificity and regulation[J].Annu Rev Biochem,2017,86:159-192
[5]Sahtoe DD,Sixma TK.Layers of DUB regulation[J].Trends Biochem Sci,2015,40(8):456-467
[6]Nijman SM,Huang TT,Dirac AM,et al.The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway[J].Mol Cell,2005,17(3):331-339
[7]Cotto-Rios XM,Jones MJ,Busino L,et al.APC/CCdh1-dependent proteolysis of USP1 regulates the response to UVmediated DNA damage[J].J Cell Biol,2011,194(2):177-186
[8]Wu HC,Lin YC,Liu CH,et al.USP11 regulates PML stability to control Notch-induced malignancy in brain tumours[J].Nat Commun,2014,5:3214
[9]Burrows JF,Mc Grattan MJ,Rascle A,et al.DUB-3,a cytokine-inducible deubiquitinating enzyme that blocks proliferation[J].J Biol Chem,2004,279(14):13993-14000
[10]Reiley W,Zhang M,Wu X,et al.Regulation of the deubiquitinating enzyme CYLD by Ikappa B kinase gammadependent phosphorylation[J].Mol Cell Biol,2005,25(10):3886-3895
[11]Tan Y,Ichikawa T,Li J,et al.Diabetic downregulation of Nrf2activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo[J].Diabetes,2011,60(2):625-633
[12]Wu N,Zhang C,Bai C,et al.MiR-4782-3p inhibited non-small cell lung cancer growth via USP14[J].Cell Physiol Biochem,2014,33(2):457-467
[13]Wu N,Liu C,Bai C,et al.Over-expression of deubiquitinating enzyme USP14 in lung adenocarcinoma promotes proliferation through the accumulation ofβ-catenin[J].Int J Mol Sci,2013,14(6):10749-10760
[14]Li J,Tan Q,Yan M,et al.miRNA-200c inhibits invasion and metastasis of human non-small cell lung cancer by directly targeting ubiquitin specific peptidase 25[J].Mol Cancer,2014,13:166
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[28]Wada K,Kamitani T.Unp EL/Usp4 is ubiquitinated by Ro52and deubiquitinated by itself[J].Biochem Biophys Res Commun,2006,342(1):253-258
[29]Meulmeester E,Kunze M,Hsiao HH,et al.Mechanism and consequences for paralog-specific sumoylation of ubiquitinspecific protease 25[J].Mol Cell,2008,30(5):610-619
[30]Kobayashi T,Masoumi KC,Massoumi R.Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells[J].Oncogene,2015,34(17):2251-2260
[31]Meray RK,Lansbury PT Jr.Reversible monoubiquitination regulates the Parkinson disease-associated ubiquitin hydrolase UCH-L1[J].J Biol Chem,2007,282(14):10567-10575
[32]Mevissen TE,Hospenthal MK,Geurink PP,et al.OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis[J].Cell,2013,154(1):169-184
[33]Tsou WL,Burr AA,Ouyang M,et al.Ubiquitination regulates the neuroprotective function of the deubiquitinase ataxin-3 in vivo[J].J Biol Chem,2013,288(48):34460-34469
[34]Almeida B,Abreu IA,Matos CA,et al.SUMOylation of the brain-predominant Ataxin-3 isoform modulates its interaction with p97[J].Biochim Biophys Acta,2015,1852(9):1950-1959
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[36]Choudhary C,Kumar C,Gnad F,et al.Lysine acetylation targets protein complexes and co-regulates major cellular functions[J].Science,2009,325(5942):834-840
[37]Cotto-Rios XM,Bekes M,Chapman J,et al.Deubiquitinases as a signaling target of oxidative stress[J].Cell Rep,2012,2(6):1475-1484
[38]Huang TT,Nijman SM,Mirchandani KD,et al.Regulation of monoubiquitinated PCNA by DUB autocleavage[J].Nat Cell Biol,2006,8(4):339-347
[39]Coornaert B,Baens M,Heyninck K,et al.T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappa B inhibitor A20[J].Nat Immunol,2008,9(3):263-271
[40]Cohn MA,Kowal P,Yang K,et al.A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway[J].Mol Cell,2007,28(5):786-797
[41]Garcia-Santisteban I,Zorroza K,Rodriguez JA.Two nuclear localization signals in USP1 mediate nuclear import of the USP1/UAF1 complex[J].PLo S One,2012,7(6):e38570
[42]Lehoux M,Gagnon D,Archambault J.E1-mediated recruitment of a UAF1-USP deubiquitinase complex facilitates human papillomavirus DNA replication[J].J Virol,2014,88(15):8545-8555
[43]Park JK,Das T,Song EJ,et al.Structural basis for recruiting and shuttling of the spliceosomal deubiquitinase USP4 by SART3[J].Nucleic Acids Res,2016,44(11):5424-5437
[44]Urbe S,Liu H,Hayes SD,et al.Systematic survey of deubiquitinase localization identifies USP21 as a regulator of centrosome-and microtubule-associated functions[J].Mol Biol Cell,2012,23(6):1095-1103
[45]Timani KA,Liu Y,Suvannasankha A,et al.Regulation of ubiquitin-proteasome system-mediated Tip110 protein degradation by USP15[J].Int J Biochem Cell Biol,2014,54:10-19
[46]Zhang Q,Harding R,Hou F,et al.Structural basis of the recruitment of ubiquitin-specific protease USP15 by spliceosome recycling factor SART3[J].J Biol Chem,2016,291(33):17283-17292
[47]Okuda H,Ohdan H,Nakayama M,et al.The USP21 short variant(USP21SV)lacking NES,located mostly in the nucleus in vivo,activates transcription by deubiquitylating ub H2A in vitro[J].PLo S One,2013,8(11):e79813
[48]Nakamura N,Hirose S.Regulation of mitochondrial morphology by USP30,a deubiquitinating enzyme present in the mitochondrial outer membrane[J].Mol Biol Cell,2008,19(5):1903-1911
[49]Endo A,Matsumoto M,Inada T,et al.Nucleolar structure and function are regulated by the deubiquitylating enzyme USP36[J].J Cell Sci,2009,122(Pt 5):678-686
[50]Eguether T,Ermolaeva MA,Zhao Y,et al.The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells[J].Nat Commun,2014,5:4585
[51]Mashtalir N,Daou S,Barbour H,et al.Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O[J].Mol Cell,2014,54(3):392-406
[52]Mc Cullough J,Row PE,Lorenzo O,et al.Activation of the endosome-associated ubiquitin isopeptidase AMSH by STAM,a component of the multivesicular body-sorting machinery[J].Curr Biol,2006,16(2):160-165
[53]Feng L,Wang J,Chen J.The Lys63-specific deubiquitinating enzyme BRCC36 is regulated by two scaffold proteins localizing in different subcellular compartments[J].J Biol Chem,2010,285(40):30982-30988
[54]Cohn MA,Kowal P,Yang K,et al.A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway[J].Mol Cell,2007,28(5):786-797
[55]Kee Y,Yang K,Cohn MA,et al.WDR20 regulates activity of the USP12 x UAF1 deubiquitinating enzyme complex[J].J Biol Chem,2010,285(15):11252-11257
[56]Yue W,Chen Z,Liu H,et al.A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30[J].Cell Res,2014,24(4):482-496
[57]Faesen AC,Dirac AM,Shanmugham A,et al.Mechanism of USP7/HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase[J].Mol Cell,2011,44(1):147-159
[58]Randles L,Anchoori RK,Roden RB,et al.The proteasome ubiquitin receptor hRpn13 and its interacting deubiquitinating enzyme Uch37 are required for proper cell cycle progression[J].J Biol Chem,2016,291(16):8773-8783
[59]Sahtoe DD,van Dijk WJ,El Oualid F,et al.Mechanism of UCH-L5 activation and inhibition by DEUBAD domains in RPN13 and INO80G[J].Mol Cell,2015,57(5):887-900
[60]Wiener R,Di Bello AT,Lombardi PM,et al.E2 ubiquitinconjugating enzymes regulate the deubiquitinating activity of OTUB1[J].Nat Struct Mol Biol,2013,20(9):1033-1039
[61]Peng Y,Xu R,Zheng X.HSCARG negatively regulates the cellular antiviral RIG-I like receptor signaling pathway by inhibiting TRAF3 ubiquitination via recruiting OTUB1[J].PLo S Pathog,2014,10(4):e1004041
[62]Wolberger C.Mechanisms for regulating deubiquitinating enzymes[J].Protein Sci,2014,23(4):344-353
[63]Zhang L,Zhou F,Drabsch Y,et al.USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-βtype I receptor[J].Nat Cell Biol,2012,14(7):717-726
[64]Yuan J,Luo K,Zhang L,et al.USP10 regulates p53localization and stability by deubiquitinating p53[J].Cell,2010,140(3):384-396
[65]Farshi P,Deshmukh RR,Nwankwo JO,et al.Deubiquitinases(DUBs)and DUB inhibitors:a patent review[J].Expert Opin Ther Pat,2015,25(10):1191-1208
[66]Jin J,Xie X,Xiao Y,et al.Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid[J].Nat Immunol,2016,17(3):259-268
[2]Citterio E.Fine-tuning the ubiquitin code at DNA double-strand breaks:deubiquitinating enzymes at work[J].Front Genet,2015,6:282
[3]Wei R,Liu X,Yu W,et al.Deubiquitinases in cancer[J].Oncotarget,2015,6(15):12872-12889
[4]Mevissen TET,Komander D.Mechanisms of deubiquitinase specificity and regulation[J].Annu Rev Biochem,2017,86:159-192
[5]Sahtoe DD,Sixma TK.Layers of DUB regulation[J].Trends Biochem Sci,2015,40(8):456-467
[6]Nijman SM,Huang TT,Dirac AM,et al.The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway[J].Mol Cell,2005,17(3):331-339
[7]Cotto-Rios XM,Jones MJ,Busino L,et al.APC/CCdh1-dependent proteolysis of USP1 regulates the response to UVmediated DNA damage[J].J Cell Biol,2011,194(2):177-186
[8]Wu HC,Lin YC,Liu CH,et al.USP11 regulates PML stability to control Notch-induced malignancy in brain tumours[J].Nat Commun,2014,5:3214
[9]Burrows JF,Mc Grattan MJ,Rascle A,et al.DUB-3,a cytokine-inducible deubiquitinating enzyme that blocks proliferation[J].J Biol Chem,2004,279(14):13993-14000
[10]Reiley W,Zhang M,Wu X,et al.Regulation of the deubiquitinating enzyme CYLD by Ikappa B kinase gammadependent phosphorylation[J].Mol Cell Biol,2005,25(10):3886-3895
[11]Tan Y,Ichikawa T,Li J,et al.Diabetic downregulation of Nrf2activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo[J].Diabetes,2011,60(2):625-633
[12]Wu N,Zhang C,Bai C,et al.MiR-4782-3p inhibited non-small cell lung cancer growth via USP14[J].Cell Physiol Biochem,2014,33(2):457-467
[13]Wu N,Liu C,Bai C,et al.Over-expression of deubiquitinating enzyme USP14 in lung adenocarcinoma promotes proliferation through the accumulation ofβ-catenin[J].Int J Mol Sci,2013,14(6):10749-10760
[14]Li J,Tan Q,Yan M,et al.miRNA-200c inhibits invasion and metastasis of human non-small cell lung cancer by directly targeting ubiquitin specific peptidase 25[J].Mol Cancer,2014,13:166
[15]Olsen JV,Blagoev B,Gnad F,et al.Global,in vivo,and sitespecific phosphorylation dynamics in signaling networks[J].Cell,2006,127(3):635-648
[16]Hutti JE,Shen RR,Abbott DW,et al.Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKKepsilon promotes cell transformation[J].Mol Cell,2009,34(4):461-472
[17]Kim S,Lee D,Lee J,et al.Vaccinia-related kinase 2 controls the stability of the eukaryotic chaperonin TRi C/CCT by inhibiting the deubiquitinating enzyme USP25[J].Mol Cell Biol,2015,35(10):1754-1762
[18]Huang X,Summers MK,Pham V,et al.Deubiquitinase USP37is activated by CDK2 to antagonize APC(CDH1)and promote S phase entry[J].Mol Cell,2011,42(4):511-523
[19]Villamil MA,Liang Q,Chen J,et al.Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1[J].Biochemistry,2012,51(45):9112-9123
[20]Olazabal-Herrero A,Garcia-Santisteban I,Rodriguez JA.Structure-function analysis of USP1:insights into the role of Ser313 phosphorylation site and the effect of cancer-associated mutations on autocleavage[J].Mol Cancer,2015,14:33
[21]Mizuno E,Kitamura N,Komada M.14-3-3-dependent inhibition of the deubiquitinating activity of UBPY and its cancellation in the M phase[J].Exp Cell Res,2007,313(16):3624-3634
[22]Reincke M,Sbiera S,Hayakawa A,et al.Mutations in the deubiquitinase gene USP8 cause Cushing’s disease[J].Nat Genet,2015,47(1):31-38
[23]Cao Z,Wu X,Yen L,et al.Neuregulin-induced Erb B3downregulation is mediated by a protein stability cascade involving the E3 ubiquitin ligase Nrdp1[J].Mol Cell Biol,2007,27(6):2180-2188
[24]Meijer IM,Kerperien J,Sotoca AM,et al.The Usp8deubiquitination enzyme is post-translationally modified by tyrosine and serine phosphorylation[J].Cell Signal,2013,25(4):919-930
[25]Huang OW,Ma X,Yin J,et al.Phosphorylation-dependent activity of the deubiquitinase DUBA[J].Nat Struct Mol Biol,2012,19(2):171-175
[26]Edelmann MJ,Kramer HB,Altun M,et al.Post-translational modification of the deubiquitinating enzyme otubain 1 modulates active Rho A levels and susceptibility to Yersinia invasion[J].FEBS J,2010,277(11):2515-2530
[27]Herhaus L,Perez-Oliva AB,Cozza G,et al.Casein kinase 2(CK2)phosphorylates the deubiquitylase OTUB1 at Ser16 to trigger its nuclear localization[J].Sci Signal,2015,8(372):ra35
[28]Wada K,Kamitani T.Unp EL/Usp4 is ubiquitinated by Ro52and deubiquitinated by itself[J].Biochem Biophys Res Commun,2006,342(1):253-258
[29]Meulmeester E,Kunze M,Hsiao HH,et al.Mechanism and consequences for paralog-specific sumoylation of ubiquitinspecific protease 25[J].Mol Cell,2008,30(5):610-619
[30]Kobayashi T,Masoumi KC,Massoumi R.Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells[J].Oncogene,2015,34(17):2251-2260
[31]Meray RK,Lansbury PT Jr.Reversible monoubiquitination regulates the Parkinson disease-associated ubiquitin hydrolase UCH-L1[J].J Biol Chem,2007,282(14):10567-10575
[32]Mevissen TE,Hospenthal MK,Geurink PP,et al.OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis[J].Cell,2013,154(1):169-184
[33]Tsou WL,Burr AA,Ouyang M,et al.Ubiquitination regulates the neuroprotective function of the deubiquitinase ataxin-3 in vivo[J].J Biol Chem,2013,288(48):34460-34469
[34]Almeida B,Abreu IA,Matos CA,et al.SUMOylation of the brain-predominant Ataxin-3 isoform modulates its interaction with p97[J].Biochim Biophys Acta,2015,1852(9):1950-1959
[35]Seki T,Gong L,Williams AJ,et al.Jos D1,a membranetargeted deubiquitinating enzyme,is activated by ubiquitination and regulates membrane dynamics,cell motility,and endocytosis[J].J Biol Chem,2013,288(24):17145-17155
[36]Choudhary C,Kumar C,Gnad F,et al.Lysine acetylation targets protein complexes and co-regulates major cellular functions[J].Science,2009,325(5942):834-840
[37]Cotto-Rios XM,Bekes M,Chapman J,et al.Deubiquitinases as a signaling target of oxidative stress[J].Cell Rep,2012,2(6):1475-1484
[38]Huang TT,Nijman SM,Mirchandani KD,et al.Regulation of monoubiquitinated PCNA by DUB autocleavage[J].Nat Cell Biol,2006,8(4):339-347
[39]Coornaert B,Baens M,Heyninck K,et al.T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappa B inhibitor A20[J].Nat Immunol,2008,9(3):263-271
[40]Cohn MA,Kowal P,Yang K,et al.A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway[J].Mol Cell,2007,28(5):786-797
[41]Garcia-Santisteban I,Zorroza K,Rodriguez JA.Two nuclear localization signals in USP1 mediate nuclear import of the USP1/UAF1 complex[J].PLo S One,2012,7(6):e38570
[42]Lehoux M,Gagnon D,Archambault J.E1-mediated recruitment of a UAF1-USP deubiquitinase complex facilitates human papillomavirus DNA replication[J].J Virol,2014,88(15):8545-8555
[43]Park JK,Das T,Song EJ,et al.Structural basis for recruiting and shuttling of the spliceosomal deubiquitinase USP4 by SART3[J].Nucleic Acids Res,2016,44(11):5424-5437
[44]Urbe S,Liu H,Hayes SD,et al.Systematic survey of deubiquitinase localization identifies USP21 as a regulator of centrosome-and microtubule-associated functions[J].Mol Biol Cell,2012,23(6):1095-1103
[45]Timani KA,Liu Y,Suvannasankha A,et al.Regulation of ubiquitin-proteasome system-mediated Tip110 protein degradation by USP15[J].Int J Biochem Cell Biol,2014,54:10-19
[46]Zhang Q,Harding R,Hou F,et al.Structural basis of the recruitment of ubiquitin-specific protease USP15 by spliceosome recycling factor SART3[J].J Biol Chem,2016,291(33):17283-17292
[47]Okuda H,Ohdan H,Nakayama M,et al.The USP21 short variant(USP21SV)lacking NES,located mostly in the nucleus in vivo,activates transcription by deubiquitylating ub H2A in vitro[J].PLo S One,2013,8(11):e79813
[48]Nakamura N,Hirose S.Regulation of mitochondrial morphology by USP30,a deubiquitinating enzyme present in the mitochondrial outer membrane[J].Mol Biol Cell,2008,19(5):1903-1911
[49]Endo A,Matsumoto M,Inada T,et al.Nucleolar structure and function are regulated by the deubiquitylating enzyme USP36[J].J Cell Sci,2009,122(Pt 5):678-686
[50]Eguether T,Ermolaeva MA,Zhao Y,et al.The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells[J].Nat Commun,2014,5:4585
[51]Mashtalir N,Daou S,Barbour H,et al.Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O[J].Mol Cell,2014,54(3):392-406
[52]Mc Cullough J,Row PE,Lorenzo O,et al.Activation of the endosome-associated ubiquitin isopeptidase AMSH by STAM,a component of the multivesicular body-sorting machinery[J].Curr Biol,2006,16(2):160-165
[53]Feng L,Wang J,Chen J.The Lys63-specific deubiquitinating enzyme BRCC36 is regulated by two scaffold proteins localizing in different subcellular compartments[J].J Biol Chem,2010,285(40):30982-30988
[54]Cohn MA,Kowal P,Yang K,et al.A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway[J].Mol Cell,2007,28(5):786-797
[55]Kee Y,Yang K,Cohn MA,et al.WDR20 regulates activity of the USP12 x UAF1 deubiquitinating enzyme complex[J].J Biol Chem,2010,285(15):11252-11257
[56]Yue W,Chen Z,Liu H,et al.A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30[J].Cell Res,2014,24(4):482-496
[57]Faesen AC,Dirac AM,Shanmugham A,et al.Mechanism of USP7/HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase[J].Mol Cell,2011,44(1):147-159
[58]Randles L,Anchoori RK,Roden RB,et al.The proteasome ubiquitin receptor hRpn13 and its interacting deubiquitinating enzyme Uch37 are required for proper cell cycle progression[J].J Biol Chem,2016,291(16):8773-8783
[59]Sahtoe DD,van Dijk WJ,El Oualid F,et al.Mechanism of UCH-L5 activation and inhibition by DEUBAD domains in RPN13 and INO80G[J].Mol Cell,2015,57(5):887-900
[60]Wiener R,Di Bello AT,Lombardi PM,et al.E2 ubiquitinconjugating enzymes regulate the deubiquitinating activity of OTUB1[J].Nat Struct Mol Biol,2013,20(9):1033-1039
[61]Peng Y,Xu R,Zheng X.HSCARG negatively regulates the cellular antiviral RIG-I like receptor signaling pathway by inhibiting TRAF3 ubiquitination via recruiting OTUB1[J].PLo S Pathog,2014,10(4):e1004041
[62]Wolberger C.Mechanisms for regulating deubiquitinating enzymes[J].Protein Sci,2014,23(4):344-353
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