Ubiquitin Makes Its Mark on Immune Regulation

Immunity

Volumn 33, Issue 6, 2010, Pages 843-852

  Malynn, Barbara A ^a   Ma, Averil ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BINDING PROTEIN; UBIQUITIN; UBIQUITIN PROTEIN LIGASE;

CELL TYPE; IMMUNOCOMPETENT CELL; IMMUNOREGULATION; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; UBIQUITINATION;

ADAPTIVE IMMUNITY; ANIMALS; HUMANS; IMMUNITY, INNATE; IMMUNOMODULATION; MICE; NF-KAPPA B; SIGNAL TRANSDUCTION; UBIQUITIN; UBIQUITIN-CONJUGATING ENZYMES;

EID: 78650090605     PISSN: 10747613     EISSN: 10974180     Source Type: Journal    
DOI: 10.1016/j.immuni.2010.12.007     Document Type: Review

References (99)

1. Abbott D.W., Wilkins A., Asara J.M., Cantley L.C. The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr. Biol. 2004, 14:2217-2227.
2. Abbott D.W., Yang Y., Hutti J.E., Madhavarapu S., Kelliher M.A., Cantley L.C. Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. Mol. Cell. Biol. 2007, 27:6012-6025.
3. Alexander W.S., Hilton D.J. The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu. Rev. Immunol. 2004, 22:503-529.
4. Anandasabapathy N., Ford G.S., Bloom D., Holness C., Paragas V., Seroogy C., Skrenta H., Hollenhorst M., Fathman C.G., Soares L. GRAIL: An E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 2003, 18:535-547.
5. Aravind L., Koonin E.V. The U box is a modified RING finger - a common domain in ubiquitination. Curr. Biol. 2000, 10:R132-R134.
6. Arimoto K., Funami K., Saeki Y., Tanaka K., Okawa K., Takeuchi O., Akira S., Murakami Y., Shimotohno K. Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense. Proc. Natl. Acad. Sci. USA 2010, 107:15856-15861.
7. Ashida H., Kim M., Schmidt-Supprian M., Ma A., Ogawa M., Sasakawa C. A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKgamma to dampen the host NF-kappaB-mediated inflammatory response. Nat. Cell Biol. 2010, 12:66-73. 1-9.
8. Bertrand M.J., Milutinovic S., Dickson K.M., Ho W.C., Boudreault A., Durkin J., Gillard J.W., Jaquith J.B., Morris S.J., Barker P.A. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. Cell 2008, 30:689-700.
9. Bhoj V.G., Chen Z.J. Ubiquitylation in innate and adaptive immunity. Nature 2009, 458:430-437.
10. Boone D.L., Turer E.E., Lee E.G., Ahmad R.C., Wheeler M.T., Tsui C., Hurley P., Chien M., Chai S., Hitotsumatsu O., et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat. Immunol. 2004, 5:1052-1060.
11. Bosanac I., Wertz I.E., Pan B., Yu C., Kusam S., Lam C., Phu L., Phung Q., Maurer B., Arnott D., et al. Ubiquitin binding to A20 ZnF4 is required for modulation of NF-κB signaling. Mol. Cell 2010, 40:548-557.
12. Bremm A., Freund S.M., Komander D. Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne. Nat. Struct. Mol. Biol. 2010, 17:939-947.
13. Carter R.S., Pennington K.N., Arrate P., Oltz E.M., Ballard D.W. Site-specific monoubiquitination of IkappaB kinase IKKbeta regulates its phosphorylation and persistent activation. J. Biol. Chem. 2005, 280:43272-43279.
14. Cejas P.J., Walsh M.C., Pearce E.L., Han D., Harms G.M., Artis D., Turka L.A., Choi Y. TRAF6 inhibits Th17 differentiation and TGF-beta-mediated suppression of IL-2. Blood 2010, 115:4750-4757.
15. Chang L., Kamata H., Solinas G., Luo J.L., Maeda S., Venuprasad K., Liu Y.C., Karin M. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell 2006, 124:601-613.
16. Chen D.J., Huerta S. Smac mimetics as new cancer therapeutics. Anticancer Drugs 2009, 20:646-658.
17. Christensen D.E., Klevit R.E. Dynamic interactions of proteins in complex networks: Identifying the complete set of interacting E2s for functional investigation of E3-dependent protein ubiquitination. FEBS J. 2009, 276:5381-5389.
18. Christensen D.E., Brzovic P.S., Klevit R.E. E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages. Nat. Struct. Mol. Biol. 2007, 14:941-948.
19. Chu Y., Vahl J.C., Kumar D., Heger K., Bertossi A., Wójtowicz E., Soberon V., Schenten D., Mack B., Reutelshöfer M., et al. B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation, hyperactivation, cause inflammation and autoimmunity in aged mice. Blood 2010.
20. Conze D.B., Zhao Y., Ashwell J.D. Non-canonical NF-κB activation and abnormal B cell accumulation in mice expressing ubiquitin protein ligase-inactive c-IAP2. PLoS Biol. 2010, 8:e1000518.
21. David Y., Ziv T., Admon A., Navon A. The E2 ubiquitin-conjugating enzymes direct polyubiquitination to preferred lysines. J. Biol. Chem. 2010, 285:8595-8604.
22. Deng L., Wang C., Spencer E., Yang L., Braun A., You J., Slaughter C., Pickart C., Chen Z.J. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 2000, 103:351-361.
23. Deshaies R.J., Joazeiro C.A. RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 2009, 78:399-434.
24. Ea C.K., Deng L., Xia Z.P., Pineda G., Chen Z.J. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol. Cell 2006, 22:245-257.
25. Fushman D., Walker O. Exploring the linkage dependence of polyubiquitin conformations using molecular modeling. J. Mol. Biol. 2010, 395:803-814.
26. Gack M.U., Shin Y.C., Joo C.H., Urano T., Liang C., Sun L., Takeuchi O., Akira S., Chen Z., Inoue S., Jung J.U. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 2007, 446:916-920.
27. Ha, H., Han, D., and Choi, Y. (2009). TRAF-mediated TNFR-family signaling. Curr. Protoc. Immunol. Chapter 11:Unit11.9D.
28. Haas T.L., Emmerich C.H., Gerlach B., Schmukle A.C., Cordier S.M., Rieser E., Feltham R., Vince J., Warnken U., Wenger T., et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol. Cell 2009, 36:831-844.
29. Hatakeyama S., Yada M., Matsumoto M., Ishida N., Nakayama K.I. U box proteins as a new family of ubiquitin-protein ligases. J. Biol. Chem. 2001, 276:33111-33120.
30. Hitotsumatsu O., Ahmad R.C., Tavares R., Wang M., Philpott D., Turer E.E., Lee B.L., Shiffin N., Advincula R., Malynn B.A., et al. The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity 2008, 28:381-390.
31. Huang H., Jeon M.S., Liao L., Yang C., Elly C., Yates J.R., Liu Y.C. K33-linked polyubiquitination of T cell receptor-zeta regulates proteolysis-independent T cell signaling. Immunity 2010, 33:60-70.
32. Kim H.T., Kim K.P., Uchiki T., Gygi S.P., Goldberg A.L. S5a promotes protein degradation by blocking synthesis of nondegradable forked ubiquitin chains. EMBO J. 2009, 28:1867-1877.
33. King C.G., Kobayashi T., Cejas P.J., Kim T., Yoon K., Kim G.K., Chiffoleau E., Hickman S.P., Walsh P.T., Turka L.A., Choi Y. TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis. Nat. Med. 2006, 12:1088-1092.
34. King C.G., Buckler J.L., Kobayashi T., Hannah J.R., Bassett G., Kim T., Pearce E.L., Kim G.G., Turka L.A., Choi Y. Cutting edge: Requirement for TRAF6 in the induction of T cell anergy. J. Immunol. 2008, 180:34-38.
35. Kirisako T., Kamei K., Murata S., Kato M., Fukumoto H., Kanie M., Sano S., Tokunaga F., Tanaka K., Iwai K. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 2006, 25:4877-4887.
36. Kirkpatrick D.S., Denison C., Gygi S.P. Weighing in on ubiquitin: The expanding role of mass-spectrometry-based proteomics. Nat. Cell Biol. 2005, 7:750-757.
37. Kirkpatrick D.S., Hathaway N.A., Hanna J., Elsasser S., Rush J., Finley D., King R.W., Gygi S.P. Quantitative analysis of in vitro ubiquitinated cyclin B1 reveals complex chain topology. Nat. Cell Biol. 2006, 8:700-710.
38. Kobayashi T., Walsh P.T., Walsh M.C., Speirs K.M., Chiffoleau E., King C.G., Hancock W.W., Caamano J.H., Hunter C.A., Scott P., et al. TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 2003, 19:353-363.
39. Kobayashi T., Kim T.S., Jacob A., Walsh M.C., Kadono Y., Fuentes-Pananá E., Yoshioka T., Yoshimura A., Yamamoto M., Kaisho T., et al. TRAF6 is required for generation of the B-1a B cell compartment as well as T cell-dependent and -independent humoral immune responses. PLoS ONE 2009, 4:e4736.
40. Komander D. The emerging complexity of protein ubiquitination. Biochem. Soc. Trans. 2009, 37:937-953.
41. Komander D., Clague M.J., Urbé S. Breaking the chains: Structure and function of the deubiquitinases. Nat. Rev. Mol. Cell Biol. 2009, 10:550-563.
42. Lee E.G., Boone D.L., Chai S., Libby S.L., Chien M., Lodolce J.P., Ma A. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 2000, 289:2350-2354.
43. Li L., Halaby M.J., Hakem A., Cardoso R., El Ghamrasni S., Harding S., Chan N., Bristow R., Sanchez O., Durocher D., Hakem R. Rnf8 deficiency impairs class switch recombination, spermatogenesis, and genomic integrity and predisposes for cancer. J. Exp. Med. 2010, 207:983-997.
44. Lin A.E., Mak T.W. The role of E3 ligases in autoimmunity and the regulation of autoreactive T cells. Curr. Opin. Immunol. 2007, 19:665-673.
45. Liu C., Qian W., Qian Y., Giltiay N.V., Lu Y., Swaidani S., Misra S., Deng L., Chen Z.J., Li X. Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci. Signal. 2009, 2:ra63.
46. Lomaga M.A., Yeh W.C., Sarosi I., Duncan G.S., Furlonger C., Ho A., Morony S., Capparelli C., Van G., Kaufman S., et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999, 13:1015-1024.
47. Malynn B.A., Ma A. A20 takes on tumors: Tumor suppression by an ubiquitin-editing enzyme. J. Exp. Med. 2009, 206:977-980.
48. Matsumoto M.L., Wickliffe K.E., Dong K.C., Yu C., Bosanac I., Bustos D., Phu L., Kirkpatrick D.S., Hymowitz S.G., Rape M., et al. K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage-specific antibody. Mol. Cell 2010, 39:477-484.
49. Micheau O., Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2003, 114:181-190.
50. Newton K., Matsumoto M.L., Wertz I.E., Kirkpatrick D.S., Lill J.R., Tan J., Dugger D., Gordon N., Sidhu S.S., Fellouse F.A., et al. Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies. Cell 2008, 134:668-678.
51. Nurieva R.I., Zheng S., Jin W., Chung Y., Zhang Y., Martinez G.J., Reynolds J.M., Wang S.L., Lin X., Sun S.C., et al. The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation. Immunity 2010, 32:670-680.
52. Oganesyan G., Saha S.K., Guo B., He J.Q., Shahangian A., Zarnegar B., Perry A., Cheng G. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 2006, 439:208-211.
53. Oshima S., Turer E.E., Callahan J.A., Chai S., Advincula R., Barrera J., Shifrin N., Lee B., Benedict Yen T.S., Yen B., et al. ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development. Nature 2009, 457:906-909.
54. Palmer D.C., Restifo N.P. Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function. Trends Immunol. 2009, 30:592-602.
55. Pickart C.M., Eddins M.J. Ubiquitin: Structures, functions, mechanisms. Biochim. Biophys. Acta 2004, 1695:55-72.
56. Pickart C.M., Fushman D. Polyubiquitin chains: Polymeric protein signals. Curr. Opin. Chem. Biol. 2004, 8:610-616.
57. Qian Y., Qin J., Cui G., Naramura M., Snow E.C., Ware C.F., Fairchild R.L., Omori S.A., Rickert R.C., Scott M., et al. Act1, a negative regulator in CD40- and BAFF-mediated B cell survival. Immunity 2004, 21:575-587.
58. Qian Y., Liu C., Hartupee J., Altuntas C.Z., Gulen M.F., Jane-Wit D., Xiao J., Lu Y., Giltiay N., Liu J., et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat. Immunol. 2007, 8:247-256.
59. Qian Y., Giltiay N., Xiao J., Wang Y., Tian J., Han S., Scott M., Carter R., Jorgensen T.N., Li X. Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjögren's syndrome. Eur. J. Immunol. 2008, 38:2219-2228.
60. Rahighi S., Ikeda F., Kawasaki M., Akutsu M., Suzuki N., Kato R., Kensche T., Uejima T., Bloor S., Komander D., et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell 2009, 136:1098-1109.
61. Reyes-Turcu F.E., Ventii K.H., Wilkinson K.D. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu. Rev. Biochem. 2009, 78:363-397.
62. Rodrigo-Brenni M.C., Foster S.A., Morgan D.O. Catalysis of lysine 48-specific ubiquitin chain assembly by residues in E2 and ubiquitin. Mol. Cell 2010, 39:548-559.
63. Rotin D., Kumar S. Physiological functions of the HECT family of ubiquitin ligases. Nat. Rev. Mol. Cell Biol. 2009, 10:398-409.
64. Rowland S.L., Tremblay M.M., Ellison J.M., Stunz L.L., Bishop G.A., Hostager B.S. A novel mechanism for TNFR-associated factor 6-dependent CD40 signaling. J. Immunol. 2007, 179:4645-4653.
65. Santos M.A., Huen M.S., Jankovic M., Chen H.T., López-Contreras A.J., Klein I.A., Wong N., Barbancho J.L., Fernandez-Capetillo O., Nussenzweig M.C., et al. Class switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8. J. Exp. Med. 2010, 207:973-981.
66. Sato Y., Yoshikawa A., Yamagata A., Mimura H., Yamashita M., Ookata K., Nureki O., Iwai K., Komada M., Fukai S. Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains. Nature 2008, 455:358-362.
67. Scheper J., Guerra-Rebollo M., Sanclimens G., Moure A., Masip I., González-Ruiz D., Rubio N., Crosas B., Meca-Cortés O., Loukili N., et al. Protein-protein interaction antagonists as novel inhibitors of non-canonical polyubiquitylation. PLoS ONE 2010, 5:e11403.
68. Sigismund S., Polo S., Di Fiore P.P. Signaling through monoubiquitination. Curr. Top. Microbiol. Immunol. 2004, 286:149-185.
69. Sims J.J., Cohen R.E. Linkage-specific avidity defines the lysine 63-linked polyubiquitin-binding preference of rap80. Mol. Cell 2009, 33:775-783.
70. Sims J.J., Haririnia A., Dickinson B.C., Fushman D., Cohen R.E. Avid interactions underlie the Lys63-linked polyubiquitin binding specificities observed for UBA domains. Nat. Struct. Mol. Biol. 2009, 16:883-889.
71. Skaug B., Jiang X., Chen Z.J. The role of ubiquitin in NF-kappaB regulatory pathways. Annu. Rev. Biochem. 2009, 78:769-796.
72. Spallek T., Robatzek S., Göhre V. How microbes utilize host ubiquitination. Cell. Microbiol. 2009, 11:1425-1434.
73. Sun S.C. Deubiquitylation and regulation of the immune response. Nat. Rev. Immunol. 2008, 8:501-511.
74. Sun L., Chen Z.J. The novel functions of ubiquitination in signaling. Curr. Opin. Cell Biol. 2004, 16:119-126.
75. Tavares R.M., Turer E.E., Liu C.L., Advincula R., Scapini P., Rhee L., Barrera J., Lowell C.A., Utz P.J., Malynn B.A., Ma A. The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity 2010, 33:181-191.
76. Tokunaga F., Sakata S., Saeki Y., Satomi Y., Kirisako T., Kamei K., Nakagawa T., Kato M., Murata S., Yamaoka S., et al. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat. Cell Biol. 2009, 11:123-132.
77. Tseng P.H., Matsuzawa A., Zhang W., Mino T., Vignali D.A., Karin M. Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat. Immunol. 2010, 11:70-75.
78. Turer E.E., Tavares R.M., Mortier E., Hitotsumatsu O., Advincula R., Lee B., Shifrin N., Malynn B.A., Ma A. Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20. J. Exp. Med. 2008, 205:451-464.
79. Vallabhapurapu S., Matsuzawa A., Zhang W., Tseng P.H., Keats J.J., Wang H., Vignali D.A., Bergsagel P.L., Karin M. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat. Immunol. 2008, 9:1364-1370.
80. Venuprasad K. Cbl-b and itch: Key regulators of peripheral T-cell tolerance. Cancer Res. 2010, 70:3009-3012.
81. Vereecke L., Sze M., Guire C.M., Rogiers B., Chu Y., Schmidt-Supprian M., Pasparakis M., Beyaert R., van Loo G. Enterocyte-specific A20 deficiency sensitizes to tumor necrosis factor-induced toxicity and experimental colitis. J. Exp. Med. 2010, 207:1513-1523.
82. Wada K., Niida M., Tanaka M., Kamitani T. Ro52-mediated monoubiquitination of IKKbeta down-regulates NF-kappaB signalling. J. Biochem. 2009, 146:821-832.
83. Walsh M.C., Kim G.K., Maurizio P.L., Molnar E.E., Choi Y. TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL. PLoS ONE 2008, 3:e4064.
84. Wang H., Matsuzawa A., Brown S.A., Zhou J., Guy C.S., Tseng P.H., Forbes K., Nicholson T.P., Sheppard P.W., Häcker H., et al. Analysis of nondegradative protein ubiquitylation with a monoclonal antibody specific for lysine-63-linked polyubiquitin. Proc. Natl. Acad. Sci. USA 2008, 105:20197-20202.
85. Wang T., Yin L., Cooper E.M., Lai M.Y., Dickey S., Pickart C.M., Fushman D., Wilkinson K.D., Cohen R.E., Wolberger C. Evidence for bidentate substrate binding as the basis for the K48 linkage specificity of otubain 1. J. Mol. Biol. 2009, 386:1011-1023.
86. Wang H., Holst J., Woo S.R., Guy C., Bettini M., Wang Y., Shafer A., Naramura M., Mingueneau M., Dragone L.L., et al. Tonic ubiquitylation controls T-cell receptor:CD3 complex expression during T-cell development. EMBO J. 2010, 29:1285-1298.
87. Wertz I.E., Dixit V.M. Signaling to NF-kappaB: Regulation by ubiquitination. Cold Spring Harb Perspect Biol 2010, 2:a003350.
88. Wertz I.E., O'Rourke K.M., Zhou H., Eby M., Aravind L., Seshagiri S., Wu P., Wiesmann C., Baker R., Boone D.L., et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 2004, 430:694-699.
89. Winget J.M., Mayor T. The diversity of ubiquitin recognition: Hot spots and varied specificity. Mol. Cell 2010, 38:627-635.
90. Wu C.J., Conze D.B., Li T., Srinivasula S.M., Ashwell J.D. Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. Nat. Cell Biol. 2006, 8:398-406.
91. Xia Z.P., Sun L., Chen X., Pineda G., Jiang X., Adhikari A., Zeng W., Chen Z.J. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature 2009, 461:114-119.
92. Xu M., Skaug B., Zeng W., Chen Z.J. A ubiquitin replacement strategy in human cells reveals distinct mechanisms of IKK activation by TNFalpha and IL-1beta. Mol. Cell 2009, 36:302-314.
93. Xu P., Duong D.M., Seyfried N.T., Cheng D., Xie Y., Robert J., Rush J., Hochstrasser M., Finley D., Peng J. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell 2009, 137:133-145.
94. Yamamoto M., Okamoto T., Takeda K., Sato S., Sanjo H., Uematsu S., Saitoh T., Yamamoto N., Sakurai H., Ishii K.J., et al. Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat. Immunol. 2006, 7:962-970.
95. Yamamoto M., Sato S., Saitoh T., Sakurai H., Uematsu S., Kawai T., Ishii K.J., Takeuchi O., Akira S. Cutting edge: Pivotal function of Ubc13 in thymocyte TCR signaling. J. Immunol. 2006, 177:7520-7524.
96. Ye Y., Rape M. Building ubiquitin chains: E2 enzymes at work. Nat. Rev. Mol. Cell Biol. 2009, 10:755-764.
97. Zeng W., Sun L., Jiang X., Chen X., Hou F., Adhikari A., Xu M., Chen Z.J. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 2010, 141:315-330.
98. Zhou H., Wertz I., O'Rourke K., Ultsch M., Seshagiri S., Eby M., Xiao W., Dixit V.M. Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature 2004, 427:167-171.
99. Zucchelli S., Codrich M., Marcuzzi F., Pinto M., Vilotti S., Biagioli M., Ferrer I., Gustincich S. TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains. Hum. Mol. Genet. 2010, 19:3759-3770.