Regulation of T Cell Differentiation and Allergic Responses by the E3 Ubiquitin Ligase Itch

  • Y.-C. Liu
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2008/1)


Itch is an E3 ubiquitin ligase that is originally identified by genetic analysis of a mutant mouse with aberrant immunological phenotypes and constant itching in the skin. Itch–/– T cells are biased toward the differentiation of T helper type 2 cells with augmented interleukin-4 cytokine production and serum IgE level. One of the mechanisms for Itch E3 ligase to regulate T cell responses is the induction of T cell anergy in which T cells become unresponsive upon restimulation. However, the detailed mechanisms underlying Itch-mediated protein ubiquitination and allergic responses remain to be investigated. Here we provide evidence that Itch is involved in the regulation of transforming growth factor (TGF)-β signaling in naïve T cells and TGF-β-induced expression of the transcription factor Foxp3, a master regulator in regulatory T cells. Itch promotes ubiquitin conjugation to TGF-β inducible early gene 1 product (TIEG1). Moreover, monoubiquitinated TIEG1 positively modulates the transcription of Foxp3 gene. The results suggest a novel mechanism by which Itch regulates regulatory T cells and subsequent allergic responses.


Protein Ubiquitination Foxp3 Expression Tolerance Induction Foxp3 Gene Cell Anergy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author thanks the contributions from postdoctoral fellows trained in this laboratory and from outside collaborators. The work on Itch project is supported by NIH funding.


  1. Anandasabapathy N, Ford GS, Bloom D, Holness C, Paragas V, Seroogy C, Skrenta H, Hollenhorst M, Fathman CG, Soares L (2003) GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 18:535–547CrossRefPubMedGoogle Scholar
  2. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–1401CrossRefPubMedGoogle Scholar
  3. Apostolou I, von Boehmer H (2004) In vivo instruction of suppressor commitment in naive T cells. J Exp Med 199:1401–1408CrossRefPubMedGoogle Scholar
  4. Attisano L, Wrana JL (2002) Signal transduction by the TGF-beta superfamily. Science 296:1646–1647CrossRefPubMedGoogle Scholar
  5. Bachmaier K, Krawczyk C, Kozieradzki I, Kong YY, Sasaki T, Oliveira-dos-Santos A, Mariathasan S, Bouchard D, Wakeham A, Itie A et al (2000) Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403:211–216CrossRefPubMedGoogle Scholar
  6. Bai Y, Yang C, Hu K, Elly C, Liu YC (2004) Itch E3 ligase-mediated regulation of TGF-beta signaling by modulating smad2 phosphorylation. Mol Cell 15:825–831CrossRefPubMedGoogle Scholar
  7. Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, Hurley P, Chien M, Chai S, Hitotsumatsu O et al (2004) The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 5:1052–1060CrossRefPubMedGoogle Scholar
  8. Chang L, Kamada H, Solinas G, Luo J, Maeda S, Venuprasad K, Liu YC, Karin M (2006) The E3 ubiquitin ligase Itch couples JNK activation to TNFa-induced cell death by inducing c-FLIPL turnover. Cell 124:601–613CrossRefPubMedGoogle Scholar
  9. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886CrossRefPubMedGoogle Scholar
  10. Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu RJ, Jang IK, Gutkind JS, Shevach E, Gu H (2000) Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403:216–220CrossRefPubMedGoogle Scholar
  11. Cornell M, Evans DA, Mann R, Fostier M, Flasza M, Monthatong M, Artavanis-Tsakonas S, Baron M (1999) The Drosophila melanogaster Suppressor of deltex gene, a regulator of the Notch receptor signaling pathway, is an E3 class ubiquitin ligase. Genetics 152:567–576PubMedGoogle Scholar
  12. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584CrossRefPubMedGoogle Scholar
  13. Fang D, Liu Y-C (2001) Proteolysis-independent regulation of phosphatidylinositol 3-kinase by Cbl-b-mediated ubiquitination in T cells. Nature Immunol 2:870–875CrossRefGoogle Scholar
  14. Fang D, Elly C, Gao B, Fang N, Altman Y, Joazeiro C, Hunter T, Copeland N, Jenkins N, Liu YC (2002) Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol 3:281–287CrossRefPubMedGoogle Scholar
  15. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF (2004) Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25 T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172:5149–5153PubMedGoogle Scholar
  16. Fields PE, Gajewski TF, Fitch FW (1996) Blocked Ras activation in anergic CD4+ T cells. Science 271:1276–1278CrossRefPubMedGoogle Scholar
  17. Gajewski TF, Qian D, Fields P, Fitch FW (1994) Anergic T-lymphocyte clones have altered inositol phosphate, calcium, and tyrosine kinase signaling pathways. Proc Natl Acad Sci U S A 91:38–42CrossRefPubMedGoogle Scholar
  18. Gao M, Labuda T, Xia Y, Gallagher E, Fang D, Liu YC, Karin M (2004) Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306:271–275CrossRefPubMedGoogle Scholar
  19. Gorelik L, Constant S, Flavell RA (2002) Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 195:1499–1505CrossRefPubMedGoogle Scholar
  20. Gorelik L, Fields PE, Flavell RA (2000) Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol 165:4773–4777PubMedGoogle Scholar
  21. Hartenstein B, Teurich S, Hess J, Schenkel J, Schorpp-Kistner M, Angel P (2002) Th2 cell-specific cytokine expression and allergen-induced airway inflammation depend on JunB. EMBO J 21:6321–6329CrossRefPubMedGoogle Scholar
  22. Hefferan TE, Reinholz GG, Rickard DJ, Johnsen SA, Waters KM, Subramaniam M, Spelsberg TC (2000) Overexpression of a nuclear protein TIEG, mimics transforming growth factor-beta action in human osteoblast cells. J Biol Chem 275:20255–20259CrossRefPubMedGoogle Scholar
  23. Heissmeyer V, Macian F, Im SH, Varma R, Feske S, Venuprasad K, Gu H, Liu YC, Dustin ML, Rao A (2004) Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol 5:255–265CrossRefPubMedGoogle Scholar
  24. Hershko A, Ciechanover A, Heller H, Haas AL, Rose IA (1980) Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis. Proc Natl Acad Sci U S A 77:1783–1786CrossRefPubMedGoogle Scholar
  25. Hicke L (2001) Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol 2:195–201CrossRefPubMedGoogle Scholar
  26. Hustad CM, Perry WL, Siracusa LD, Rasberry C, Cobb L, Cattanach BM, Kovatch R, Copeland NG, Jenkins NA (1995) Molecular genetic characterization of six recessive viable alleles of the mouse agouti locus. Genetics 140:255–265PubMedGoogle Scholar
  27. Izzi L, Attisano L (2004) Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation. Oncogene 23:2071–2078CrossRefPubMedGoogle Scholar
  28. Jeon MS, Atfield A, Venuprasad K, Krawczyk C, Sarao R, Elly C, Yang C, Arya S, Bachmaier K, Su L et al (2004) Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity 21:167–177CrossRefPubMedGoogle Scholar
  29. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6:1219–1227CrossRefPubMedGoogle Scholar
  30. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S (1993) Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A 90:770–774CrossRefPubMedGoogle Scholar
  31. Li B, Tournier C, Davis RJ, Flavell RA (1999) Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation. EMBO J 18:420–432CrossRefPubMedGoogle Scholar
  32. Li MO, Sanjabi S, Flavell RA (2006) Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25:455–471CrossRefPubMedGoogle Scholar
  33. Li W, Whaley CD, Mondino A, Mueller DL (1996) Blocked signal transduction to the ERK and JNK protein kinases in anergic CD4+ T cells. Science 271:1272–1276CrossRefPubMedGoogle Scholar
  34. Liu YC (2004) Ubiquitin ligases and the immune response. Annu Rev Immunol 22:81–127CrossRefPubMedGoogle Scholar
  35. Liu YC (2007) The E3 ubiquitin ligase Itch in T cell activation, differentiation, and tolerance. Semin Immunol 19:197–205CrossRefPubMedGoogle Scholar
  36. Liu YC, Penninger J, Karin M (2005) Immunity by ubiquitylation: a reversible process of modification. Nat Rev Immunol 5:941–952CrossRefPubMedGoogle Scholar
  37. Marie JC, Liggitt D, Rudensky AY (2006) Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25:441–454CrossRefPubMedGoogle Scholar
  38. McMenamin C, Pimm C, McKersey M, Holt PG (1994) Regulation of IgE responses to inhaled antigen in mice by antigen-specific gamma delta T cells. Science 265:1869–1871CrossRefPubMedGoogle Scholar
  39. Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille JJ, Curotto de Lafaille MA (2005) Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest 115:1923–1933CrossRefPubMedGoogle Scholar
  40. Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123:773–786CrossRefPubMedGoogle Scholar
  41. Ostroukhova M, Seguin-Devaux C, Oriss TB, Dixon-McCarthy B, Yang L, Ameredes BT, Corcoran TE, Ray A (2004) Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta and FOXP3. J Clin Invest 114:28–38PubMedGoogle Scholar
  42. Perry WL, Hustad CM, Swing DA, O'Sullivan TN, Jenkins NA, Copeland NG (1998) The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in α18H mice [see comments]. Nat Genet 18:143–146CrossRefPubMedGoogle Scholar
  43. Pickart CM (2001) Mechanisms underlying ubiquitination. Annu Rev Biochem 70:503–533CrossRefPubMedGoogle Scholar
  44. Qiu L, Joazeiro C, Fang N, Wang HY, Elly C, Altman Y, Fang D, Hunter T, Liu YC (2000) Recognition and ubiquitination of Notch by Itch, a Hect-type E3 ubiquitin ligase. J Biol Chem 275:35734–35737CrossRefPubMedGoogle Scholar
  45. Reiley WW, Zhang M, Jin W, Losiewicz M, Donohue KB, Norbury CC, Sun SC (2006) Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 7:411–417CrossRefPubMedGoogle Scholar
  46. Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562CrossRefPubMedGoogle Scholar
  47. Schwartz RH (2003) T cell anergy. Annu Rev Immunol 21:305–334CrossRefPubMedGoogle Scholar
  48. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359:693–699CrossRefPubMedGoogle Scholar
  49. Venuprasad K, Elly C, Gao M, Salek-Ardakani S, Harada Y, Luo JL, Yang C, Croft M, Inoue K, Karin M, Liu YC (2006) Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation. J Clin Invest 116:1117–1126CrossRefPubMedGoogle Scholar
  50. Venuprasad K, Huang H, Harada Y, Elly C, Malayannan S, Spelsberg T, Su J, Liu YC (2008) The E3 ubiquitin ligase Itch regulates Foxp3 expression and airway inflammation via enhancing the function of transcription factor TIEG1. Nat Immunol 9:245–253CrossRefPubMedGoogle Scholar
  51. Walker LS, Abbas AK (2002) The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol 2:11–19CrossRefPubMedGoogle Scholar
  52. Wan YY, Flavell RA (2005) Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci U S A 102:5126–5131CrossRefPubMedGoogle Scholar
  53. Wan YY, Flavell RA (2007) Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445:766–770CrossRefPubMedGoogle Scholar
  54. Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821–852CrossRefPubMedGoogle Scholar
  55. Weissman AM (2001) Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol 2:169–178CrossRefPubMedGoogle Scholar
  56. Yang C, Zhou W, Jeon MS, Demydenko D, Harada Y, Zhou H, Liu YC (2006) Negative regulation of the E3 ubiquitin ligase Itch via Fyn-mediated tyrosine phosphorylation. Mol Cell 21:135–141CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Division of Cell BiologyLa Jolla Institute for Allergy and ImmunologyLa JollaUSA

Personalised recommendations