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Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation

Nature Immunology volume 3, pages 281–287 (2002)Cite this article

Abstract

Itch is an E3 ubiquitin ligase that is disrupted in nonagouti-lethal or itchy mice. Itch deficiency leads to severe immune and inflammatory disorders and constant itching of the skin. Here we show that Itch−/− T cells show an activated phenotype and enhanced proliferation. Production of the type 2 T helper (TH2) cell cytokines interleukin 4 (IL-4) and IL-5 by Itch−/− T cells was augmented upon stimulation, and the TH2-dependent serum concentrations of immunoglobulin G1 (IgG1) and IgE in itchy mice were also increased. Molecularly, Itch associated with and induced ubiquitination of JunB, a transcription factor that is involved in TH2 differentiation. These results provide a molecular link between Itch deficiency and the aberrant activation of immune responses in itchy mice.

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Figure 1: Flow cytometric analysis of Itch−/− and wild-type mice.
Figure 2: Cell proliferation and cytokine production of primary T cells from Itch−/− and wild-type mice.
Figure 3: Increased serum IgG1 and IgE concentrations in Itch−/− mice.
Figure 4: T cell activation in Itch−/− T cells.
Figure 5: JunB ubiquitination by Itch.
Figure 6: JunB protein expression and its DNA binding in Itch−/− T cells.

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References

  1. Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).

    Article  CAS  Google Scholar 

  2. Hicke, L. Gettin' down with ubiquitin: turning off cell-surface receptors, transporters and channels. Trends Cell Biol. 9, 107–112 (1999).

    Article  CAS  Google Scholar 

  3. Kaiser, P., Flick, K., Wittenberg, C. & Reed, S. I. Regulation of transcription by ubiquitination without proteolysis: Cdc34/SCF(Met30)-mediated inactivation of the transcription factor Met4. Cell 102, 303–314 (2000).

    Article  CAS  Google Scholar 

  4. Hoppe, T. et al. Activation of a membrane-bound transcription factor by regulated ubiquitin/proteasome-dependent processing. Cell 102, 577–586 (2000).

    Article  CAS  Google Scholar 

  5. Fang, D. & Liu, Y.-C. Proteolysis-independent regulation of phosphatidylinositol 3-kinase by Cbl-b-mediated ubiquitination in T cells. Nature Immunol. 2, 870–875 (2001).

    Article  CAS  Google Scholar 

  6. Deng, L. et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103, 351–361 (2000).

    Article  CAS  Google Scholar 

  7. Kishino, T., Lalande, M. & Wagstaff, J. UBE3A/E6-AP mutations cause Angelman syndrome. Nature Genet. 15, 70–73 (1997).

    Article  CAS  Google Scholar 

  8. Shimura, H. et al. Ubiquitination of a new form of α-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293, 263–269 (2001).

    Article  CAS  Google Scholar 

  9. Imai, Y. et al. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891–902 (2001).

    Article  CAS  Google Scholar 

  10. Hustad, C. M. et al. Molecular genetic characterization of six recessive viable alleles of the mouse agouti locus. Genetics 140, 255–265 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Perry, W. L. et al. The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nature Genet. 18, 143–146 (1998).

    Article  CAS  Google Scholar 

  12. Sudol, M. & Hunter, T. NeW wrinkles for an old domain. Cell 103, 1001–1004 (2000).

    Article  CAS  Google Scholar 

  13. Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).

    Article  CAS  Google Scholar 

  14. Paul, W. E. & Seder, R. A. Lymphocyte responses and cytokines. Cell 76, 241–251 (1994).

    Article  CAS  Google Scholar 

  15. Qiu, L. et al. Recognition and ubiquitination of Notch by Itch, a Hect-type E3 ubiquitin Ligase. J. Biol. Chem. 275, 35734–35737 (2000).

    Article  CAS  Google Scholar 

  16. Robson MacDonald, H., Wilson, A. & Radtke, F. Notch1 and T-cell development: insights from conditional knockout mice. Trends Immunol. 22, 155–160 (2001).

    Article  Google Scholar 

  17. Shultz, L. D. et al. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73, 1445–1454 (1993).

    Article  CAS  Google Scholar 

  18. Tsui, H. W., Siminovitch, K. A., de Souza, L. & Tsui, F. W. Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nature Genet. 4, 124–129 (1993).

    Article  CAS  Google Scholar 

  19. Healy, J. I. & Goodnow, C. C. Positive versus negative signaling by lymphocyte antigen receptors. Annu. Rev. Immunol. 16, 645–670 (1998).

    Article  CAS  Google Scholar 

  20. Li, B., Tournier, C., Davis, R. J. & Flavell, R. A. Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation. EMBO J. 18, 420–432 (1999).

    Article  Google Scholar 

  21. Abbas, A. K., Murphy, K. M. & Sher, A. Functional diversity of helper T lymphocytes. Nature 383, 787–793 (1996).

    Article  CAS  Google Scholar 

  22. Romagnani, S. The Th1/Th2 paradigm. Immunol. Today 18, 263–266 (1997).

    Article  CAS  Google Scholar 

  23. Ho, I. C., Hodge, M. R., Rooney, J. W. & Glimcher, L. H. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell 85, 973–983 (1996).

    Article  CAS  Google Scholar 

  24. Zheng, W. & Flavell, R. A. The transcription factor GATA-3 is necessary and sufficient for TH2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).

    Article  CAS  Google Scholar 

  25. Szabo, S. J. et al. A novel transcription factor, T-bet, directs TH1 lineage commitment. Cell 100, 655–669 (2000).

    Article  CAS  Google Scholar 

  26. Mullen, A. C. et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292, 1907–1910 (2001).

    Article  CAS  Google Scholar 

  27. Sperling, A. I. & Bluestone, J. A. ICOS costimulation: it's not just for TH2 cells anymore. Nature Immunol. 2, 573–574 (2001).

    Article  CAS  Google Scholar 

  28. Treier, M., Staszewski, L. M. & Bohmann, D. Ubiquitin-dependent c-Jun degradation in vivo is mediated by the δ domain. Cell 78, 787–798 (1994).

    Article  CAS  Google Scholar 

  29. Fang, D. et al. Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J. Biol. Chem. 276, 4872–4878 (2001).

    Article  CAS  Google Scholar 

  30. Joazeiro, C. A. et al. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science 286, 309–312 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Altman, Y. Tanaka, M. Jeon and others at the Division of Cell Biology for support and suggestions. Supported by grants from National Institutes of Health (RO1DK56558) and American Cancer Society (to Y.-C. L.).

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Authors and Affiliations

  1. Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, 92121, CA, USA

    Deyu Fang, Chris Elly, Baixue Gao, Nan Fang, Yoav Altman & Yun-Cai Liu

  2. The Salk Institute, La Jolla, 92037, CA, USA

    Claudio Joazeiro & Tony Hunter

  3. National Cancer Institute, Frederick, 21702, MA, USA

    Neal Copeland & Nancy Jenkins

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  1. Deyu Fang
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Correspondence to Yun-Cai Liu.

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Supplementary information

Web Figure 1.

Effect of Itch on reporter-based transactivation. Jurkat cells were transfected with either AP-1- or NF-κB–driven luciferase reporter in the absence or the presence of wild-type Itch or Itch CA mutant. The relative luciferase activity was normalized and presented as fold increase over the basal activity. Thirty hours after transfection, cells were left untreated or stimulated with anti-CD3 for 6 h, collected and washed twice with PBS. Luciferase activity in the cell extracts was determined in triplicate by luminometry. Each experiment was repeated at least three times. (GIF 11 kb)

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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 3, 281–287 (2002). https://doi.org/10.1038/ni763

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