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Cbl- and Nedd4-family ubiquitin ligases: balancing tolerance and immunity

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Abstract

Engagement of the T cell receptor (TCR) with its cognate peptide/MHC initiates a cascade of signaling events that results in T cell activation. Limiting the extent and duration of TCR signaling ensures a tightly constrained response, protecting cells from the deleterious impact of chronic activation. In order to limit the duration of activation, T cells must adjust levels of key signaling proteins. This can be accomplished by altering protein synthesis or by changing the rate of protein degradation. Ubiquitination is a process of ‘tagging’ a protein with ubiquitin and is one means of initiating protein degradation. This process is activated when an E3 ubiquitin ligase mediates the transfer of ubiquitin to a target protein. Accordingly, E3 ubiquitin ligases have recently emerged as key regulators of immune cell function. This review will explore how a small group of E3 ubiquitin ligases regulate T cell responses and thus direct adaptive immunity.

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References

  1. Staub O, Rotin D. Role of ubiquitylation in cellular membrane transport. Physiol Rev. 2006;86:669–707.

    Article  PubMed  CAS  Google Scholar 

  2. Pickart CM, Eddins MJ. Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta. 2004;1695:55–72.

    Article  PubMed  CAS  Google Scholar 

  3. Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem. 2001;70:503–33.

    Article  PubMed  CAS  Google Scholar 

  4. Nandi D, Tahiliani P, Kumar A, et al. The ubiquitin-proteasome system. J Biosci. 2006;31:137–55.

    Article  PubMed  CAS  Google Scholar 

  5. Liu YC. Ubiquitin ligases and the immune response. Annu Rev Immunol. 2004;22:81–127.

    Article  PubMed  CAS  Google Scholar 

  6. Liu YC, Penninger J, Karin M. Immunity by ubiquitylation: a reversible process of modification. Nat Rev Immunol. 2005;5:941–52.

    Article  PubMed  CAS  Google Scholar 

  7. Duan L, Reddi AL, Ghosh A, et al. The Cbl family and other ubiquitin ligases: destructive forces in control of antigen receptor signaling. Immunity. 2004;21:7–17.

    Article  PubMed  CAS  Google Scholar 

  8. Cronin SJ, Penninger JM. From T-cell activation signals to signaling control of anti-cancer immunity. Immunol Rev. 2007;220:151–68.

    Article  PubMed  CAS  Google Scholar 

  9. Mueller DL. E3 ubiquitin ligases as T cell anergy factors. Nat Immunol. 2004;5:883–90.

    Article  PubMed  CAS  Google Scholar 

  10. Bonnevier JL, Zhang R, Mueller DL. E3 ubiquitin ligases and their control of T cell autoreactivity. Arthritis Res Ther. 2005;7:233–42.

    Article  PubMed  CAS  Google Scholar 

  11. Heissmeyer V, Macian F, Varma R, et al. A molecular dissection of lymphocyte unresponsiveness induced by sustained calcium signalling. Novartis Found Symp. 2005;267:165–74. Discussion 169–74.

    Article  PubMed  CAS  Google Scholar 

  12. Lin AE, Mak TW. The role of E3 ligases in autoimmunity and the regulation of autoreactive T cells. Curr Opin Immunol. 2007;19:665–73.

    Article  PubMed  CAS  Google Scholar 

  13. Rudd CE, Schneider H. Lymphocyte signaling: Cbl sets the threshold for autoimmunity. Curr Biol. 2000;10:R344–7.

    Article  PubMed  CAS  Google Scholar 

  14. Rao N, Dodge I, Band H. The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune system. J Leukoc Biol. 2002;71:753–63.

    PubMed  CAS  Google Scholar 

  15. Heissmeyer V, Rao A. E3 ligases in T cell anergy–turning immune responses into tolerance. Sci STKE. 2004;2004:pe29.

  16. Swaminathan G, Tsygankov AY. The Cbl family proteins: ring leaders in regulation of cell signaling. J Cell Physiol. 2006;209:21–43.

    Article  PubMed  CAS  Google Scholar 

  17. Schmidt MH, Dikic I. The Cbl interactome and its functions. Nat Rev Mol Cell Biol. 2005;6:907–18.

    Article  PubMed  CAS  Google Scholar 

  18. Peschard P, Kozlov G, Lin T, et al. Structural basis for ubiquitin-mediated dimerization and activation of the ubiquitin protein ligase Cbl-b. Mol Cell. 2007;27:474–85.

    Article  PubMed  CAS  Google Scholar 

  19. Davies GC, Ettenberg SA, Coats AO, et al. Cbl-b interacts with ubiquitinated proteins; differential functions of the UBA domains of c-Cbl and Cbl-b. Oncogene. 2004;23:7104–15.

    Article  PubMed  CAS  Google Scholar 

  20. Woelk T, Oldrini B, Maspero E, et al. Molecular mechanisms of coupled monoubiquitination. Nat Cell Biol. 2006;8:1246–54.

    Article  PubMed  CAS  Google Scholar 

  21. Zhang D, Raasi S, Fushman D. Affinity makes the difference: nonselective interaction of the UBA domain of Ubiquilin-1 with monomeric ubiquitin and polyubiquitin chains. J Mol Biol. 2008;377:162–80.

    Article  PubMed  CAS  Google Scholar 

  22. Ingham RJ, Gish G, Pawson T. The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture. Oncogene. 2004;23:1972–84.

    Article  PubMed  CAS  Google Scholar 

  23. Nalefski EA, Falke JJ. The C2 domain calcium-binding motif: structural and functional diversity. Protein Sci. 1996;5:2375–90.

    Article  PubMed  CAS  Google Scholar 

  24. Plant PJ, Lafont F, Lecat S, et al. Apical membrane targeting of Nedd4 is mediated by an association of its C2 domain with annexin XIIIb. J Cell Biol. 2000;149:1473–84.

    Article  PubMed  CAS  Google Scholar 

  25. Morrione A, Plant P, Valentinis B, et al. mGrb10 interacts with Nedd4. J Biol Chem. 1999;274:24094–9.

    Article  PubMed  CAS  Google Scholar 

  26. Monami G, Emiliozzi V, Morrione A. Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization. J Cell Physiol. 2008;216:426–37.

    Article  PubMed  CAS  Google Scholar 

  27. Yamaguchi K, Ohara O, Ando A, et al. Smurf1 directly targets hPEM-2, a GEF for Cdc42, via a novel combination of protein interaction modules in the ubiquitin-proteasome pathway. Biol Chem. 2008;389:405–13.

    Article  PubMed  CAS  Google Scholar 

  28. Wiesner S, Ogunjimi AA, Wang HR, et al. Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain. Cell. 2007;130:651–62.

    Article  PubMed  CAS  Google Scholar 

  29. Bruce C, Kanelis V, Fouladkou F, et al. Regulation of Nedd4-2 self-ubiquitylation and stability by a PY motif located within its HECT-domain. Biochem J. 2008.

  30. Gallagher E, Gao M, Liu YC, et al. Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change. Proc Natl Acad Sci USA. 2006;103:1717–22.

    Article  PubMed  CAS  Google Scholar 

  31. Ingham RJ, Colwill K, Howard C, et al. WW domains provide a platform for the assembly of multiprotein networks. Mol Cell Biol. 2005;25:7092–106.

    Article  PubMed  CAS  Google Scholar 

  32. Otte L, Wiedemann U, Schlegel B, et al. WW domain sequence activity relationships identified using ligand recognition propensities of 42 WW domains. Protein Sci. 2003;12:491–500.

    Article  PubMed  CAS  Google Scholar 

  33. Pickart CM, Fushman D. Polyubiquitin chains: polymeric protein signals. Curr Opin Chem Biol. 2004;8:610–6.

    Article  PubMed  CAS  Google Scholar 

  34. Kim HT, Kim KP, Lledias F, et al. Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages. J Biol Chem. 2007;282:17375–86.

    Article  PubMed  CAS  Google Scholar 

  35. Thien CB, Langdon WY. c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses. Biochem J. 2005;391:153–66.

    Article  PubMed  CAS  Google Scholar 

  36. Naramura M, Jang IK, Kole H, et al. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat Immunol. 2002;3:1192–9.

    Article  PubMed  CAS  Google Scholar 

  37. Wiedemann A, Muller S, Favier B, et al. T-cell activation is accompanied by an ubiquitination process occurring at the immunological synapse. Immunol Lett. 2005;98:57–61.

    Article  PubMed  CAS  Google Scholar 

  38. Bachmaier K, Krawczyk C, Kozieradzki I, et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature. 2000;403:211–6.

    Article  PubMed  CAS  Google Scholar 

  39. Fang D, Liu YC. Proteolysis-independent regulation of PI3 K by Cbl-b-mediated ubiquitination in T cells. Nat Immunol. 2001;2:870–5.

    Article  PubMed  CAS  Google Scholar 

  40. Fang D, Wang HY, Fang N, et al. Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J Biol Chem. 2001;276:4872–8.

    Article  PubMed  CAS  Google Scholar 

  41. Heissmeyer V, Macian F, Im SH, et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol. 2004;5:255–65.

    Article  PubMed  CAS  Google Scholar 

  42. Jeon MS, Atfield A, Venuprasad K, et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity. 2004;21:167–77.

    Article  PubMed  CAS  Google Scholar 

  43. Jennings MD, Blankley RT, Baron M, et al. Specificity and autoregulation of Notch binding by tandem WW domains in suppressor of Deltex. J Biol Chem. 2007;282:29032–42.

    Article  PubMed  CAS  Google Scholar 

  44. Magnifico A, Ettenberg S, Yang C, et al. WW domain HECT E3 s target Cbl RING finger E3s for proteasomal degradation. J Biol Chem. 2003;278:43169–77.

    Article  PubMed  CAS  Google Scholar 

  45. Liu YC. The E3 ubiquitin ligase Itch in T cell activation, differentiation, and tolerance. Semin Immunol. 2007;19:197–205.

    Article  PubMed  CAS  Google Scholar 

  46. Perry WL, Hustad CM, Swing DA, et al. The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nat Genet. 1998;18:143–6.

    Article  PubMed  CAS  Google Scholar 

  47. Fang D, Elly C, Gao B, et al. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol. 2002;3:281–7.

    Article  PubMed  CAS  Google Scholar 

  48. Li B, Tournier C, Davis RJ, et al. Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation. Embo J. 1999;18:420–32.

    Article  PubMed  Google Scholar 

  49. Hartenstein B, Teurich S, Hess J, et al. Th2 cell-specific cytokine expression and allergen-induced airway inflammation depend on JunB. Embo J. 2002;21:6321–9.

    Article  PubMed  CAS  Google Scholar 

  50. Gao M, Labuda T, Xia Y, et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science. 2004;306:271–5.

    Article  PubMed  CAS  Google Scholar 

  51. Li H, Lin X. Positive and negative signaling components involved in TNFalpha-induced NF-kappaB activation. Cytokine. 2008;41:1–8.

    Article  PubMed  CAS  Google Scholar 

  52. Wertz IE, O’Rourke KM, Zhou H, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature. 2004;430:694–9.

    Article  PubMed  CAS  Google Scholar 

  53. Shembade N, Harhaj NS, Parvatiyar K, et al. The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20. Nat Immunol. 2008;9:254–62.

    Article  PubMed  CAS  Google Scholar 

  54. Oeckinghaus A, Wegener E, Welteke V, et al. Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation. Embo J. 2007;26:4634–45.

    Article  PubMed  CAS  Google Scholar 

  55. Wu CJ, Ashwell JD. NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation. Proc Natl Acad Sci USA. 2008;105:3023–8.

    Article  PubMed  CAS  Google Scholar 

  56. Coornaert B, Baens M, Heyninck K, et al. T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol. 2008;9:263–71.

    Article  PubMed  CAS  Google Scholar 

  57. Venuprasad K, Huang H, Harada Y, et al. The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat Immunol. 2008;9:245–53.

    Article  PubMed  CAS  Google Scholar 

  58. Rubtsov YP, Rudensky AY. TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol. 2007;7:443–53.

    Article  PubMed  CAS  Google Scholar 

  59. Zheng Y, Rudensky AY. Foxp3 in control of the regulatory T cell lineage. Nat Immunol. 2007;8:457–62.

    Article  PubMed  CAS  Google Scholar 

  60. Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol. 2008;9:239–44.

    Article  PubMed  CAS  Google Scholar 

  61. Izcue A, Coombes JL, Powrie F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev. 2006;212:256–71.

    Article  PubMed  CAS  Google Scholar 

  62. Li B, Greene MI. Special regulatory T-cell review: FOXP3 biochemistry in regulatory T cells—how diverse signals regulate suppression. Immunology. 2008;123:17–9.

    Article  PubMed  CAS  Google Scholar 

  63. Fouladkou F, Landry T, Kawabe H, et al. The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization. Proc Natl Acad Sci USA. 2008;105:8585–90.

    Article  PubMed  CAS  Google Scholar 

  64. Yang B, Gaj D, Macleod MKL, et al. Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbtb in activated T cells. Nat Immunol (in press).

  65. Shearwin-Whyatt L, Dalton HE, Foot N, et al. Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins. Bioessays. 2006;28:617–28.

    Article  PubMed  CAS  Google Scholar 

  66. Venuprasad K, Elly C, Gao M, et al. Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation. J Clin Invest. 2006;116:1117–26.

    Article  PubMed  CAS  Google Scholar 

  67. Yang C, Zhou W, Jeon MS, et al. Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation. Mol Cell. 2006;21:135–41.

    Article  PubMed  CAS  Google Scholar 

  68. Jolliffe CN, Harvey KF, Haines BP, et al. Identification of multiple proteins expressed in murine embryos as binding partners for the WW domains of the ubiquitin-protein ligase Nedd4. Biochem J. 2000;351(Pt 3):557–65.

    Google Scholar 

  69. Murillas R, Simms KS, Hatakeyama S, et al. Identification of developmentally expressed proteins that functionally interact with Nedd4 ubiquitin ligase. J Biol Chem. 2002;277:2897–907.

    Article  PubMed  CAS  Google Scholar 

  70. Harvey KF, Shearwin-Whyatt LM, Fotia A, et al. N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein. J Biol Chem. 2002;277:9307–17.

    Article  PubMed  CAS  Google Scholar 

  71. Oliver PM, Cao X, Worthen GS, et al. Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation. Immunity. 2006;25:929–40.

    Article  PubMed  CAS  Google Scholar 

  72. Shearwin-Whyatt LM, Brown DL, Wylie FG, et al. N4WBP5A (Ndfip2), a Nedd4-interacting protein, localizes to multivesicular bodies and the Golgi, and has a potential role in protein trafficking. J Cell Sci. 2004;117:3679–89.

    Article  PubMed  CAS  Google Scholar 

  73. Oberst A, Malatesta M, Aqeilan RI, et al. The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch. Proc Natl Acad Sci USA. 2007;104:11280–5.

    Article  PubMed  CAS  Google Scholar 

  74. Murdaca J, Treins C, Monthouel-Kartmann MN, et al. Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation. J Biol Chem. 2004;279:26754–61.

    Article  PubMed  CAS  Google Scholar 

  75. Dumont C, Blanchard N, Di Bartolo V, et al. TCR/CD3 down-modulation and zeta degradation are regulated by ZAP-70. J Immunol. 2002;169:1705–12.

    PubMed  CAS  Google Scholar 

  76. Davanture S, Leignadier J, Milani P, et al. Selective defect in antigen-induced TCR internalization at the immune synapse of CD8 T cells bearing the ZAP-70(Y292F) mutation. J Immunol. 2005;175:3140–9.

    PubMed  CAS  Google Scholar 

  77. Andoniou CE, Lill NL, Thien CB, et al. The Cbl proto-oncogene product negatively regulates the Src-family tyrosine kinase Fyn by enhancing its degradation. Mol Cell Biol. 2000;20:851–67.

    Article  PubMed  CAS  Google Scholar 

  78. Miura-Shimura Y, Duan L, Rao NL, et al. Cbl-mediated ubiquitinylation and negative regulation of Vav. J Biol Chem. 2003;278:38495–504.

    Article  PubMed  CAS  Google Scholar 

  79. Rao N, Miyake S, Reddi AL, et al. Negative regulation of Lck by Cbl ubiquitin ligase. Proc Natl Acad Sci USA. 2002;99:3794–9.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. The Children’s Hospital of Philadelphia, Joseph Stokes, Jr. Research Institute, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA

    Denise L. Gay, Hilda Ramón & Paula M. Oliver

  2. University of Pennsylvania, Philadelphia , PA, USA

    Hilda Ramón & Paula M. Oliver

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  1. Denise L. Gay
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  2. Hilda Ramón
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  3. Paula M. Oliver
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Correspondence to Paula M. Oliver.

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Gay, D.L., Ramón, H. & Oliver, P.M. Cbl- and Nedd4-family ubiquitin ligases: balancing tolerance and immunity. Immunol Res 42, 51–64 (2008). https://doi.org/10.1007/s12026-008-8034-0

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