Ubiquitylation within signaling pathways in- and outside of inflammation

 

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Summary

Ubiquitin is a highly conserved 76-amino-acid peptide that becomes covalently attached to lysine residues of target proteins. Since ubiquitin itself contains seven lysine residues, ubiquitin molecules can generate different types of polyubiquitin chains. Lys48-linked polyubiquitylation is well-known as posttrans-lational tag for targeting proteins for degradation by the 26S proteasome. Recent studies have revealed several new functions of ubiquitin, e.g. activation of protein kinases, control of gene transcription, DNA repair and replication, intracellular trafficking and virus budding. These functions are mainly mediated by Lys63 polyubiquitin chains or attachment of a single ubiquitin molecule to one or several lysine residues within the target protein. Importantly, protein ubiquitylation exhibits inducibility, reversibilty and recognition by specialized ubiquitin-binding domains, features similar to protein phosphorylation. In this review we comprehensively describe regulations of protein ubiquitylation and their impact on distinct signaling pathways.

^* Current address: Weill Medical College of Cornell University, Department of Neurology and Neuroscience, Division of Neurobiology, 411 East 69^th Street, New York, NY 10021, USA

• References

• 1 Hershko A, Ciechanover A, Varshavsky A. Basic Medical Research Award. The ubiquitin system. Nat Med 2000; 6: 1073-1081.
  CrossrefPubMedGoogle Scholar
• 2 McGrath JP, Jentsch S, Varshavsky A. UBA 1: an essential yeast gene encoding ubiquitin-activating enzyme. Embo J 1991; 10: 227-236.
  PubMedGoogle Scholar
• 3 Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem 2001; 70: 503-533.
  CrossrefPubMedGoogle Scholar
• 4 Wilkinson KD. Ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome. Semin Cell Dev Biol 2000; 11: 141-148.
  CrossrefPubMedGoogle Scholar
• 5 Wing SS. Deubiquitinating enzymes--the importance of driving in reverse along the ubiquitin-proteasome pathway. Int J Biochem Cell Biol 2003; 35: 590-605.
  CrossrefPubMedGoogle Scholar
• 6 Schwartz DC, Hochstrasser M. A superfamily of protein tags: ubiquitin, SUMO and related modifiers. Trends Biochem Sci 2003; 28: 321-328.
  CrossrefPubMedGoogle Scholar
• 7 Deshaies RJ. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu Rev Cell Dev Biol 1999; 15: 435-467.
  CrossrefPubMedGoogle Scholar
• 8 Malakhova OA, Yan M, Malakhov MP. et al. Protein ISGylation modulates the JAK-STAT signaling pathway. Genes Dev 2003; 17: 455-460.
  CrossrefPubMedGoogle Scholar
• 9 Pickart CM, Eddins MJ. Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta 2004; 1695: 55-72.
  CrossrefPubMedGoogle Scholar
• 10 Hicke L, Dunn R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu Rev Cell Dev Biol 2003; 19: 141-172.
  CrossrefPubMedGoogle Scholar
• 11 Haupt Y, Maya R, Kazaz A. et al. Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296-299.
  CrossrefPubMedGoogle Scholar
• 12 Jackson PK, Eldridge AG, Freed E. et al. The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol 2000; 10: 429-439.
  CrossrefPubMedGoogle Scholar
• 13 Petroski MD, Deshaies RJ. Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 2005; 6: 9-20.
  PubMedGoogle Scholar
• 14 Huibregtse JM, Scheffner M, Howley PM. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. Embo J 1991; 10: 4129-4135.
  PubMedGoogle Scholar
• 15 Scheffner M, Huibregtse JM, Vierstra RD. et al. The HPV-16 E6 and E6-AP complex functions as a ubiquitin- protein ligase in the ubiquitination of p53. Cell 1993; 75: 495-505.
  CrossrefPubMedGoogle Scholar
• 16 Huibregtse JM, Scheffner M, Beaudenon S. et al. A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci USA 1995; 92: 2563-2567.
  CrossrefPubMedGoogle Scholar
• 17 Rotin D. WW (WWP) domains: from structure to function. Curr Top Microbiol Immunol 1998; 228: 115-133.
  PubMedGoogle Scholar
• 18 Dikic I, Szymkiewicz I, Soubeyran P. Cbl signaling networks in the regulation of cell function. Cell Mol Life Sci 2003; 60: 1805-1827.
  CrossrefPubMedGoogle Scholar
• 19 Thien CB, Langdon WY. Cbl: many adaptations to regulate protein tyrosine kinases. Nat Rev Mol Cell Biol 2001; 2: 294-307.
  PubMedGoogle Scholar
• 20 Pickart CM, Fushman D. Polyubiquitin chains: polymeric protein signals. Curr Opin Chem Biol 2004; 8: 610-606.
  CrossrefPubMedGoogle Scholar
• 21 Schnell JD, Hicke L. Non-traditional functions of ubiquitin and ubiquitin-binding proteins. J Biol Chem 2003; 278: 35857-35860.
  CrossrefPubMedGoogle Scholar
• 22 Hicke L, Schubert HL, Hill CP. Ubiquitin-binding domains. Nat Rev Mol Cell Biol 2005; 6: 610-621.
  CrossrefPubMedGoogle Scholar
• 23 Polo S, Sigismund S, Faretta M. et al. A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 2002; 416: 451-455.
  CrossrefPubMedGoogle Scholar
• 24 Wilkinson CR, Seeger M, Hartmann-Petersen R. et al. Proteins containing the UBA domain are able to bind to multi-ubiquitin chains. Nat Cell Biol 2001; 3: 939-943.
  CrossrefPubMedGoogle Scholar
• 25 Madura K. The ubiquitin-associated (UBA) domain: on the path from prudence to prurience. Cell Cycle 2002; 1: 235-244.
  PubMedGoogle Scholar
• 26 Lima CD. CUE'd up for monoubiquitin. Cell 2003; 113: 554-556.
  CrossrefPubMedGoogle Scholar
• 27 Sancho E, Vila MR, Sanchez-Pulido L. et al. Role of UEV-1, an inactive variant of the E2 ubiquitin-conjugating enzymes, in in vitro differentiation and cell cycle behavior of HT-29-M6 intestinal mucosecretory cells. Mol Cell Biol 1998; 18: 576-589.
  CrossrefPubMedGoogle Scholar
• 28 Bonifacino JS, Traub LM. Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 2003; 72: 395-447.
  CrossrefPubMedGoogle Scholar
• 29 Grossman SR, Deato ME, Brignone C. et al. Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science 2003; 300: 342-344.
  CrossrefPubMedGoogle Scholar
• 30 Yokouchi M, Kondo T, Sanjay A. et al. Src-catalyzed phosphorylation of c-Cbl leads to the interdependent ubiquitination of both proteins. J Biol Chem 2001; 276: 35185-35193.
  CrossrefPubMedGoogle Scholar
• 31 Holler D, Dikic I. Receptor endocytosis via ubiquitin- dependent and -independent pathways. Biochem Pharmacol 2004; 67: 1013-1017.
  CrossrefPubMedGoogle Scholar
• 32 Haglund K, Sigismund S, Polo S. et al. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol 2003; 5: 461-466.
  CrossrefPubMedGoogle Scholar
• 33 Benmerah A, Poupon V, Cerf-Bensussan N. et al. Mapping of Eps15 domains involved in its targeting to clathrin-coated pits. J Biol Chem 2000; 275: 3288-3295.
  CrossrefPubMedGoogle Scholar
• 34 Gruenberg J. The endocytic pathway: a mosaic of domains. Nat Rev Mol Cell Biol 2001; 2: 721-730.
  CrossrefPubMedGoogle Scholar
• 35 Hofmann K, Falquet L. A ubiquitin-interacting motif conserved in components of the proteasomal and lysosomal protein degradation systems. Trends Biochem Sci 2001; 26: 347-350.
  CrossrefPubMedGoogle Scholar
• 36 Di Guglielmo GM, Le Roy C, Goodfellow AF. et al. Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol 2003; 5: 410-421.
  CrossrefPubMedGoogle Scholar
• 37 Miaczynska M, Pelkmans L, Zerial M. Not just a sink: endosomes in control of signal transduction. Curr Opin Cell Biol 2004; 16: 400-406.
  CrossrefPubMedGoogle Scholar
• 38 Zhang Y, Moheban DB, Conway BR. et al. Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. J Neurosci 2000; 20: 5671-5678.
  CrossrefPubMedGoogle Scholar
• 39 Vieira AV, Lamaze C, Schmid SL. Control of EGF receptor signaling by clathrin-mediated endocytosis. Science 1996; 274: 2086-2089.
  CrossrefPubMedGoogle Scholar
• 40 Sorkin A, Von Zastrow M. Signal transduction and endocytosis: close encounters of many kinds. Nat Rev Mol Cell Biol 2002; 3: 600-614.
  CrossrefPubMedGoogle Scholar
• 41 Sigismund S, Woelk T, Puri C. et al. Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci USA 2005; 102: 2760-2765.
  CrossrefPubMedGoogle Scholar
• 42 Baldwin Jr AS. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 1996; 14: 649-683.
  CrossrefPubMedGoogle Scholar
• 43 Pahl HL. Activators and target genes of Rel/NFkappaB transcription factors. Oncogene 1999; 18: 6853-6866.
  CrossrefPubMedGoogle Scholar
• 44 DiDonato JA, Hayakawa M, Rothwarf DM. et al. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 1997; 388: 548-554.
  CrossrefPubMedGoogle Scholar
• 45 Hatakeyama S, Kitagawa M, Nakayama K. et al. Ubiquitin- dependent degradation of IkappaBalpha is mediated by a ubiquitin ligase Skp1/Cul 1/F-box protein FWD1. Proc Natl Acad Sci USA 1999; 96: 3859-3863.
  CrossrefPubMedGoogle Scholar
• 46 Henkel T, Machleidt T, Alkalay I. et al. Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B. Nature 1993; 365: 182-185.
  CrossrefPubMedGoogle Scholar
• 47 Palombella VJ, Rando OJ, Goldberg AL. et al. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 1994; 78: 773-785.
  CrossrefPubMedGoogle Scholar
• 48 Lin L, DeMartino GN, Greene WC. Cotranslational biogenesis of NF-kappaB p50 by the 26S proteasome. Cell 1998; 92: 819-828.
  CrossrefPubMedGoogle Scholar
• 49 Orian A, Gonen H, Bercovich B. et al. SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase. Embo J 2000; 19: 2580-2591.
  CrossrefPubMedGoogle Scholar
• 50 Sears C, Olesen J, Rubin D. et al. NF-kappa B p105 processing via the ubiquitin-proteasome pathway. J Biol Chem 1998; 273: 1409-1419.
  CrossrefPubMedGoogle Scholar
• 51 Senftleben U, Cao Y, Xiao G. et al. Activation by IKKalpha of a second, evolutionary conserved, N kappa B signaling pathway. Science 2001; 293: 1495-1499.
  CrossrefPubMedGoogle Scholar
• 52 Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 2001; 7: 401-409.
  CrossrefPubMedGoogle Scholar
• 53 Amir RE, Haecker H, Karin M. et al. Mechanism of processing of the NF-kappa B2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of NEDD8-modification on the SCF(beta-TrCP) ubiquitin ligase. Oncogene 2004; 23: 2540-2547.
  CrossrefPubMedGoogle Scholar
• 54 Chung JY, Park YC, Ye H. et al. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci 2002; 115: 679-688.
  PubMedGoogle Scholar
• 55 Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science 2002; 296: 1634-1635.
  CrossrefPubMedGoogle Scholar
• 56 Hsu H, Huang J, Shu HB. et al. TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 1996; 4: 387-396.
  CrossrefPubMedGoogle Scholar
• 57 Ting AT, Pimentel-Muinos FX, Seed B. RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis. Embo J 1996; 15: 6189-6196.
  PubMedGoogle Scholar
• 58 Wu CJ, Conze DB, Li T. et al. NEMO is a sensor of Lys 63-linked polyubiquitination and functions in NFkappaB activation. Nat Cell Biol 2006; 8: 398-406.
  CrossrefPubMedGoogle Scholar
• 59 Ea CK, Deng L, Xia ZP. et al. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell 2006; 22: 245-257.
  CrossrefPubMedGoogle Scholar
• 60 Deng L, Wang C, Spencer E. et al. 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.
  CrossrefPubMedGoogle Scholar
• 61 Wang C, Deng L, Hong M. et al. TAK1 is a ubiquitin- dependent kinase of MKK and IKK. Nature 2001; 412: 346-351.
  CrossrefPubMedGoogle Scholar
• 62 Kanayama A, Seth RB, Sun L. et al. TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Mol Cell 2004; 15: 535-548.
  CrossrefPubMedGoogle Scholar
• 63 Kobayashi N, Kadono Y, Naito A. et al. Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. Embo J 2001; 20: 1271-1280.
  CrossrefPubMedGoogle Scholar
• 64 Andersen PL, Zhou H, Pastushok L. et al. Distinct regulation of Ubc13 functions by the two ubiquitinconjugating enzyme variants Mms2 and Uev1A. J Cell Biol 2005; 170: 745-755.
  CrossrefPubMedGoogle Scholar
• 65 Habelhah H, Takahashi S, Cho SG. et al. Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF-kappaB. Embo J 2004; 23: 322-332.
  CrossrefPubMedGoogle Scholar
• 66 Yamamoto M, Okamoto T, Takeda K. et al. Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat Immunol 2006; 7: 962-970.
  CrossrefPubMedGoogle Scholar
• 67 Sun L, Deng L, Ea CK. et al. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell 2004; 14: 289-301.
  CrossrefPubMedGoogle Scholar
• 68 Zhou H, Wertz I, O'Rourke K. et al. Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature 2004; 427: 167-171.
  CrossrefPubMedGoogle Scholar
• 69 Huang TT, Wuerzberger-Davis SM, Wu ZH. et al. Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell 2003; 115: 565-576.
  CrossrefPubMedGoogle Scholar
• 70 Brummelkamp TR, Nijman SM, Dirac AM. et al. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 2003; 424: 797-801.
  CrossrefPubMedGoogle Scholar
• 71 Kovalenko A, Chable-Bessia C, Cantarella G. et al. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 2003; 424: 801-805.
  CrossrefPubMedGoogle Scholar
• 72 Trompouki E, Hatzivassiliou E, Tsichritzis T. et al. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 2003; 424: 793-796.
  CrossrefPubMedGoogle Scholar
• 73 Vaux DL, Silke J. IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 2005; 6: 287-297.
  CrossrefPubMedGoogle Scholar
• 74 Reiley WW, Zhang M, Jin W. et al. Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 2006; 7: 411-417.
  CrossrefPubMedGoogle Scholar
• 75 Massoumi R, Chmielarska K, Hennecke K. et al. Cyld inhibits tumor cell proliferation by blocking Bcl- 3-dependent NF-kappaB signaling. Cell 2006; 125: 665-677.
  CrossrefPubMedGoogle Scholar
• 76 Evans PC, Ovaa H, Hamon M. et al. Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity. Biochem J 2004; 378: 727-734.
  CrossrefPubMedGoogle Scholar
• 77 Wertz IE, O'Rourke KM, Zhou H. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 2004; 430: 694-699.
  CrossrefPubMedGoogle Scholar
• 78 Makarova KS, Aravind L, Koonin EV. A novel superfamily of predicted cysteine proteases from euka eukaryotes, viruses and Chlamydia pneumoniae. Trends Biochem Sci 2000; 25: 50-52.
  CrossrefPubMedGoogle Scholar
• 79 Opipari Jr AW, Boguski MS, Dixit VM. The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type of zinc finger protein. J Biol Chem 1990; 265: 14705-14708.
  PubMedGoogle Scholar
• 80 Beyaert R, Heyninck K, Van Huffel S. A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis. Biochem Pharmacol 2000; 60: 1143-1151.
  CrossrefPubMedGoogle Scholar
• 81 Lee EG, Boone DL, Chai S. et al. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 2000; 289: 2350-2354.
  CrossrefPubMedGoogle Scholar
• 82 Boone DL, Turer EE, Lee EG. et al. The ubiquitinmodifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 2004; 5: 1052-1060.
  CrossrefPubMedGoogle Scholar
• 83 Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 2000; 12: 171-181.
  CrossrefPubMedGoogle Scholar
• 84 Shull MM, Ormsby I, Kier AB. et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992; 359: 693-699.
  CrossrefPubMedGoogle Scholar
• 85 Massague J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. Embo J 2000; 19: 1745-1754.
  CrossrefPubMedGoogle Scholar
• 86 Lin X, Liang M, Feng XH. Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. J Biol Chem 2000; 275: 36818-36822.
  CrossrefPubMedGoogle Scholar
• 87 Zhu H, Kavsak P, Abdollah S. et al. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 1999; 400: 687-693.
  CrossrefPubMedGoogle Scholar
• 88 Bonni S, Wang HR, Causing CG. et al. TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nat Cell Biol 2001; 3: 587-595.
  CrossrefPubMedGoogle Scholar
• 89 Zhang Y, Chang C, Gehling DJ. et al. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci USA 2001; 98: 974-979.
  CrossrefPubMedGoogle Scholar
• 90 Kavsak P, Rasmussen RK, Causing CG. et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 2000; 6: 1365-1375.
  CrossrefPubMedGoogle Scholar
• 91 Bai Y, Yang C, Hu K. et al. Itch E3 ligase-mediated regulation of TGF-beta signaling by modulating smad2 phosphorylation. Mol Cell 2004; 15: 825-831.
  CrossrefPubMedGoogle Scholar