Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Regulation of T cell development by the deubiquitinating enzyme CYLD

Nature Immunology volume 7, pages 411–417 (2006)Cite this article

Abstract

T cell receptor signaling is essential for the generation and maturation of T lymphocyte precursors. Here we identify the deubiquitinating enzyme CYLD as a positive regulator of proximal T cell receptor signaling in thymocytes. CYLD physically interacted with active Lck and promoted recruitment of active Lck to its substrate, Zap70. CYLD also removed both Lys 48– and Lys 63–linked polyubiquitin chains from Lck. Because of a cell-autonomous defect in T cell development, CYLD-deficient mice had substantially fewer mature CD4+ and CD8+ single-positive thymocytes and peripheral T cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: CYLD in innate immune receptor signaling.
Figure 2: T cell development in Cyld−/− mice.
Figure 3: TCR signaling in Cyld −/− thymocytes.
Figure 4: CYLD-mediated Lck-Zap70 association.
Figure 5: CYLD-mediated deubiquitination of Lck.

Similar content being viewed by others

References

  1. Germain, R.N. T-cell development and the CD4–CD8 lineage decision. Nat. Rev. Immunol. 2, 309–322 (2002).

    Article  CAS  Google Scholar 

  2. Starr, T.K., Jameson, S.C. & Hogquist, K.A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).

    Article  CAS  Google Scholar 

  3. Zamoyska, R. & Lovatt, M. Signalling in T-lymphocyte development: integration of signalling pathways is the key. Curr. Opin. Immunol. 16, 191–196 (2004).

    Article  CAS  Google Scholar 

  4. Palacios, E.H. & Weiss, A. Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene 23, 7990–8000 (2004).

    Article  CAS  Google Scholar 

  5. Gallegos, A.M. & Bevan, M.J. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039–1049 (2004).

    Article  CAS  Google Scholar 

  6. Kane, L.P., Lin, J. & Weiss, A. Signal transduction by the TCR for antigen. Curr. Opin. Immunol. 12, 242–249 (2000).

    Article  CAS  Google Scholar 

  7. Duplay, P., Thome, M., Herve, F. & Acuto, O. p56lck interacts via its src homology 2 domain with the Zap70 kinase. J. Exp. Med. 179, 1163–1172 (1994).

    Article  CAS  Google Scholar 

  8. Thome, M., Duplay, P., Guttinger, M. & Acuto, O. Syk and Zap70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/ζ complex. J. Exp. Med. 181, 1997–2006 (1995).

    Article  CAS  Google Scholar 

  9. Straus, D.B., Chan, A.C., Patai, B. & Weiss, A. SH2 domain function is essential for the role of the Lck tyrosine kinase in T cell receptor signal transduction. J. Biol. Chem. 271, 9976–9981 (1996).

    Article  CAS  Google Scholar 

  10. Pelosi, M. et al. Tyrosine 319 in the interdomain B of Zap70 is a binding site for the Src homology 2 domain of Lck. J. Biol. Chem. 274, 14229–14237 (1999).

    Article  CAS  Google Scholar 

  11. Trobridge, P.A., Forbush, K.A. & Levin, S.D. Positive and negative selection of thymocytes depends on Lck interaction with the CD4 and CD8 coreceptors. J. Immunol. 166, 809–818 (2001).

    Article  CAS  Google Scholar 

  12. Bignell, G.R. et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nat. Genet. 25, 160–165 (2000).

    Article  CAS  Google Scholar 

  13. Brooke, H.G. Epithelioma adenoides cysticum. Br. J. Dermatol. 4, 269–287 (1892).

    Google Scholar 

  14. Spiegler, E. Ueber endotheliome der haut. Arch. Derm. Syph. 50, 163–176 (1899).

    Article  Google Scholar 

  15. Biggs, P.J. et al. Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12-q13: evidence for its role as a tumour suppressor gene. Nat. Genet. 11, 441–443 (1995).

    Article  CAS  Google Scholar 

  16. Biggs, P.J., Chapman, P., Lakhani, S.R., Burn, J. & Stratton, M.R. The cylindromatosis gene (cyld1) on chromosome 16q may be the only tumour suppressor gene involved in the development of cylindromas. Oncogene 12, 1375–1377 (1996).

    CAS  PubMed  Google Scholar 

  17. Brummelkamp, T.R., Nijman, S.M., Dirac, A.M. & Bernards, R. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB. Nature 424, 797–801 (2003).

    Article  CAS  Google Scholar 

  18. Kovalenko, A. et al. The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination. Nature 424, 801–805 (2003).

    Article  CAS  Google Scholar 

  19. Trompouki, E. et al. CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members. Nature 424, 793–796 (2003).

    Article  CAS  Google Scholar 

  20. Kim, J.H., Park, K.C., Chung, S.S., Bang, O. & Chung, CH. Deubiquitinating enzymes as cellular regulators. J. Biochem. 134, 9–18 (2003).

    Article  CAS  Google Scholar 

  21. Amerik, A.Y. & Hochstrasser, M. Mechanism and function of deubiquitinating enzymes. Biochim. Biophys. Acta 1695, 189–207 (2004).

    Article  CAS  Google Scholar 

  22. Regamey, A. et al. The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor κB activation by tumor necrosis factor. J. Exp. Med. 198, 1959–1964 (2003).

    Article  CAS  Google Scholar 

  23. Reiley, W., Zhang, M. & Sun, S.-C. Tumor suppressor negatively regulates Jnk signaling pathway downstream of TNFR members. J. Biol. Chem. 279, 55161–55167 (2004).

    Article  CAS  Google Scholar 

  24. Yoshida, H., Jono, H., Kai, H. & Li, J.D. The tumor suppressor CYLD acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 and TRAF7. J. Biol. Chem. 280, 41111–41121 (2005).

    Article  CAS  Google Scholar 

  25. Tarakhovsky, A., Muller, W. & Rajewsky, K. Lymphocyte populations and immune responses in CD5-deficient mice. Eur. J. Immunol. 24, 1678–1684 (1994).

    Article  CAS  Google Scholar 

  26. Azzam, H.S. et al. Fine tuning of TCR signaling by CD5. J. Immunol. 166, 5464–5472 (2001).

    Article  CAS  Google Scholar 

  27. Fischer, A.M., Katayama, C.D., Pages, G., Pouyssegur, J. & Hedrick, S.M. The role of Erk1 and Erk2 in multiple stages of T cell development. Immunity 23, 431–443 (2005).

    Article  CAS  Google Scholar 

  28. Liu, X. & Bosselut, R. Duration of TCR signaling controls CD4–CD8 lineage differentiation in vivo. Nat. Immunol. 5, 280–288 (2004).

    Article  CAS  Google Scholar 

  29. Giannini, A. & Bijlmakers, M.J. Regulation of the Src family kinase Lck by Hsp90 and ubiquitination. Mol. Cell. Biol. 24, 5667–5676 (2004).

    Article  CAS  Google Scholar 

  30. Rao, N. et al. Negative regulation of Lck by Cbl ubiquitin ligase. Proc. Natl. Acad. Sci. USA 99, 3794–3799 (2002).

    Article  CAS  Google Scholar 

  31. Chau, V. et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243, 1576–1583 (1989).

    Article  CAS  Google Scholar 

  32. Galan, J.M. & Haguenauer-Tsapis, R. Ubiquitin Lys63 is involved in ubiquitination of a yeast plasma membrane protein. EMBO J. 16, 5847–5854 (1997).

    Article  CAS  Google Scholar 

  33. Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001).

    Article  CAS  Google Scholar 

  34. Fischer, J.A. Deubiquitinating enzymes: their roles in development, differentiation, and disease. Int. Rev. Cytol. 229, 43–72 (2003).

    Article  CAS  Google Scholar 

  35. D'Andrea, A. & Pellman, D. Deubiquitinating enzymes: a new class of biological regulators. Crit. Rev. Biochem. Mol. Biol. 33, 337–352 (1998).

    Article  CAS  Google Scholar 

  36. Chung, C.H. & Back, S.H. Deubiquitinating enzymes: their diversity and emerging roles. Biochem. Biophys. Res. Commun. 266, 633–640 (1999).

    Article  CAS  Google Scholar 

  37. Liu, Y.C. Ubiquitin ligases and the immune response. Annu. Rev. Immunol. 22, 81–127 (2004).

    Article  Google Scholar 

  38. Murphy, M.A. et al. Tissue hyperplasia and enhanced T-cell signalling via Zap70 in c-Cbl-deficient mice. Mol. Cell. Biol. 18, 4872–4882 (1998).

    Article  CAS  Google Scholar 

  39. Naramura, M., Kole, H.K., Hu, R.J. & Gu, H. Altered thymic positive selection and intracellular signals in Cbl-deficient mice. Proc. Natl. Acad. Sci. USA 95, 15547–15552 (1998).

    Article  CAS  Google Scholar 

  40. Heissmeyer, V. et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat. Immunol. 5, 255–265 (2004).

    Article  CAS  Google Scholar 

  41. Jeon, M.-S. et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity 21, 167–177 (2004).

    Article  CAS  Google Scholar 

  42. Fang, D. & Liu, Y.C. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nat. Immunol. 2, 870–875 (2001).

    Article  CAS  Google Scholar 

  43. Hawash, I.Y., Kesavan, K.P., Magee, A.I., Geahlen, R.L. & Harrison, M.L. The Lck SH3 domain negatively regulates localization to lipid rafts through an interaction with c-Cbl. J. Biol. Chem. 277, 5683–5691 (2002).

    Article  CAS  Google Scholar 

  44. Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J.C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl. Acad. Sci. USA 90, 8424–8428 (1993).

    Article  CAS  Google Scholar 

  45. Ettenberg, S.A. et al. cbl-b inhibits epidermal growth factor receptor signaling. Oncogene 18, 1855–1866 (1999).

    Article  CAS  Google Scholar 

  46. Xiao, G. et al. Retroviral oncoprotein Tax induces processing of NF-κB2/p100 in T cells: evidence for the involvement of IKKα. EMBO J. 20, 6805–6815 (2001).

    Article  CAS  Google Scholar 

  47. Waterfield, M., Zhang, M., Norman, L.P. & Sun, S.C. NF-κB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. Mol. Cell 11, 685–694 (2003).

    Article  CAS  Google Scholar 

  48. Racoosin, E.L. & Swanson, J.A. Macrophage colony-stimulating factor (rM-CSF) stimulates pinocytosis in bone marrow-derived macrophages. J. Exp. Med. 170, 1635–1648 (1989).

    Article  CAS  Google Scholar 

  49. Uhlik, M. et al. NF-κB-inducing kinase and IκB kinase participate in human T-cell leukemia virus I Tax-mediated NF-κB activation. J. Biol. Chem. 273, 21132–21136 (1998).

    Article  CAS  Google Scholar 

  50. Sun, S.-C., Ganchi, P.A., Ballard, D.W. & Greene, W.C. NF-κB controls expression of inhibitor IκBα: evidence for an inducible autoregulatory pathway. Science 259, 1912–1915 (1993).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank T. Saunders and E. Hughes of the University of Michigan Transgenic Core (Ann Arbor, Michigan) for the production of CYLD chimera mice; N. Sheaffer, A. Stanley and J. Bednarczyk of the Pennsylvania State College of Medicine Core facilities (Hershey, Pennsylvania) for assistance with flow cytometry, oligonucleotide synthesis and DNA sequencing; A. Nagy, R. Nagy and W. Abramow-Newerly of Mount Sinai Hospital (New York, New York) for the R1 embryonic stem cells; H. Band (Northwestern University, Chicago, Illinois), S. Lipkowitz (National Cancer Institute, Bethesda, Maryland) and Z. Chen (University of Texas Southwestern Medical Center, Dallas, Texas) for providing Lck, c-Cbl and ubiquitin expression vectors, respectively; and J. Lee for critical reading of the manuscript. Supported by National Institutes of Health (AI057555 to S.C.S. and M.Y.Z.; CA94922 to S.C.S.; AI056094 to C.C.N.; and C06 RR-15428-01 to the Pennsylvania State College of Medicine Animal Facility).

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, 17033, Pennsylvania, USA

    William W Reiley, Minying Zhang, Wei Jin, Mandy Losiewicz, Keri B Donohue, Christopher C Norbury & Shao-Cong Sun

Authors
  1. William W Reiley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Minying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mandy Losiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keri B Donohue
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christopher C Norbury
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shao-Cong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shao-Cong Sun.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Generation of Cyld−/− mice. (PDF 78 kb)

Supplementary Fig. 2

Surface phenotype of wild-type and Cyld−/− thymocytes. (PDF 90 kb)

Supplementary Fig. 3

Purity of isolated DP thymocytes. (PDF 101 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reiley, W., Zhang, M., Jin, W. et al. Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 7, 411–417 (2006). https://doi.org/10.1038/ni1315

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1315

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing