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:

The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity

Nature Immunology volume 12, pages 1002–1009 (2011)Cite this article

Subjects

This article has been updated

Abstract

T cell activation is subject to tight regulation to avoid inappropriate responses to self antigens. Here we show that genetic deficiency in the ubiquitin ligase Peli1 caused hyperactivation of T cells and rendered T cells refractory to suppression by regulatory T cells and transforming growth factor-β (TGF-β). As a result, Peli1-deficient mice spontaneously developed autoimmunity characterized by multiorgan inflammation and autoantibody production. Peli1 deficiency resulted in the nuclear accumulation of c-Rel, a member of the NF-κB family of transcription factors with pivotal roles in T cell activation. Peli1 negatively regulated c-Rel by mediating its Lys48 (K48) ubiquitination. Our results identify Peli1 as a critical factor in the maintenance of peripheral T cell tolerance and demonstrate a previously unknown mechanism of c-Rel regulation.

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: Peli1-deficient T cells are hyper-responsive to TCR and CD28 signals.
Figure 2: A cell-autologous role for Peli1 in regulating T cell homeostasis in vivo.
Figure 3: Peli1 deficiency renders naive T cells refractory to suppression by Treg cells and TGF-β.
Figure 4: Spontaneous development of signs of autoimmune disease by Peli1−/− mice.
Figure 5: Peli1 deficiency causes hyperactivation of late-phase NF-κB.
Figure 6: Peli1 negatively regulates c-Rel.
Figure 7: Peli1 induces ubiquitination of c-Rel.

Similar content being viewed by others

Change history

  • 20 September 2011

    In the version of this article initially published, in the Online Methods subsection "Analysis of TCR-proximal signaling," the catalog number for goat antibody to hamster immunoglobulin was incorrect. The correct number is 127-005-160. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Smith-Garvin, J.E., Koretzky, G.A. & Jordan, M.S. T cell activation. Annu. Rev. Immunol. 27, 591–619 (2009).

    Article  CAS  Google Scholar 

  2. Goodnow, C.C., Sprent, J., Fazekas de St Groth, B. & Vinuesa, C.G. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 435, 590–597 (2005).

    Article  CAS  Google Scholar 

  3. Tzachanis, D., Lafuente, E.M., Li, L. & Boussiotis, V.A. Intrinsic and extrinsic regulation of T lymphocyte quiescence. Leuk. Lymphoma 45, 1959–1967 (2004).

    Article  CAS  Google Scholar 

  4. von Boehmer, H. Mechanisms of suppression by suppressor T cells. Nat. Immunol. 6, 338–344 (2005).

    Article  CAS  Google Scholar 

  5. Sojka, D.K., Huang, Y.H. & Fowell, D.J. Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target. Immunology 124, 13–22 (2008).

    Article  CAS  Google Scholar 

  6. Lu, L.F. & Rudensky, A. Molecular orchestration of differentiation and function of regulatory T cells. Genes Dev. 23, 1270–1282 (2009).

    Article  CAS  Google Scholar 

  7. Wan, Y.Y. Regulatory T cells: immune suppression and beyond. Cell Mol. Immunol. 7, 204–210 (2010).

    Article  CAS  Google Scholar 

  8. Wells, A.D. New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J. Immunol. 182, 7331–7341 (2009).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  10. Hayden, M.S. & Ghosh, S. Shared principles in NF-κB signaling. Cell 132, 344–362 (2008).

    Article  CAS  Google Scholar 

  11. Vallabhapurapu, S. & Karin, M. Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).

    Article  CAS  Google Scholar 

  12. Köntgen, F. et al. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoural immunity, and interleukin-2 expression. Genes Dev. 9, 1965–1977 (1995).

    Article  Google Scholar 

  13. Liou, H.C. et al. c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function. Int. Immunol. 11, 361–371 (1999).

    Article  CAS  Google Scholar 

  14. Hilliard, B.A. et al. Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation. J. Clin. Invest. 110, 843–850 (2002).

    Article  CAS  Google Scholar 

  15. Mason, N.J., Liou, H.C. & Hunter, C.A. T cell-intrinsic expression of c-Rel regulates Th1 cell responses essential for resistance to Toxoplasma gondii. J. Immunol. 172, 3704–3711 (2004).

    Article  CAS  Google Scholar 

  16. Banerjee, D., Liou, H.C. & Sen, R. c-Rel-dependent priming of naive T cells by inflammatory cytokines. Immunity 23, 445–458 (2005).

    Article  CAS  Google Scholar 

  17. Chen, G. et al. Regulation of the IL-21 gene by the NF-κB transcription factor c-Rel. J. Immunol. 185, 2350–2359 (2010).

    Article  CAS  Google Scholar 

  18. Deenick, E.K. et al. c-Rel phenocopies PKCθ but not Bcl-10 in regulating CD8+ T-cell activation versus tolerance. Eur. J. Immunol. 40, 867–877 (2010).

    Article  CAS  Google Scholar 

  19. Maggirwar, S.B., Harhaj, E.W. & Sun, S.-C. Regulation of the interleukin-2 CD28 responsive element by NF-ATp and various NF-κB/Rel transcription factors. Mol. Cell Biol. 17, 2605–2614 (1997).

    Article  CAS  Google Scholar 

  20. Zhou, X.Y. et al. Molecular mechanisms underlying differential contribution of CD28 versus non-CD28 costimulatory molecules to IL-2 promoter activation. J. Immunol. 168, 3847–3854 (2002).

    Article  CAS  Google Scholar 

  21. Sen, R. & Smale, S.T. Selectivity of the NF-κB response. Cold Spring Harb. Perspect. Biol. 2, a000257 (2009).

    PubMed  Google Scholar 

  22. Bhoj, V.G. & Chen, Z.J. Ubiquitylation in innate and adaptive immunity. Nature 458, 430–437 (2009).

    Article  CAS  Google Scholar 

  23. Loeser, S. & Penninger, J.M. Regulation of peripheral T cell tolerance by the E3 ubiquitin ligase Cbl-b. Semin. Immunol. 19, 206–214 (2007).

    Article  CAS  Google Scholar 

  24. Huang, F. & Gu, H. Negative regulation of lymphocyte development and function by the Cbl family of proteins. Immunol. Rev. 224, 229–238 (2008).

    Article  CAS  Google Scholar 

  25. Butler, M.P., Hanly, J.A. & Moynagh, P.N. Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligases. J. Biol. Chem. 282, 29729–29737 (2007).

    Article  CAS  Google Scholar 

  26. Ordureau, A. et al. The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1. Biochem. J. 409, 43–52 (2008).

    Article  CAS  Google Scholar 

  27. Schauvliege, R., Janssens, S. & Beyaert, R. Pellino proteins are more than scaffold proteins in TLR/IL-1R signalling: a role as novel RING E3-ubiquitin-ligases. FEBS Lett. 580, 4697–4702 (2006).

    Article  CAS  Google Scholar 

  28. Schauvliege, R., Janssens, S. & Beyaert, R. Pellino proteins: novel players in TLR and IL-1R signalling. J. Cell Mol. Med. 11, 453–461 (2007).

    Article  CAS  Google Scholar 

  29. Moynagh, P.N. The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling. Trends Immunol. 30, 33–42 (2009).

    Article  CAS  Google Scholar 

  30. Chang, M., Jin, W. & Sun, S.C. Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production. Nat. Immunol. 10, 1089–1095 (2009).

    Article  CAS  Google Scholar 

  31. Li, M.O., Wan, Y.Y., Sanjabi, S., Robertson, A.K. & Flavell, R.A. Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol. 24, 99–146 (2006).

    Article  CAS  Google Scholar 

  32. Rubtsov, Y.P. & Rudensky, A.Y. TGFβ signalling in control of T-cell-mediated self-reactivity. Nat. Rev. Immunol. 7, 443–453 (2007).

    Article  CAS  Google Scholar 

  33. Appleman, L.J. & Boussiotis, V.A. T cell anergy and costimulation. Immunol. Rev. 192, 161–180 (2003).

    Article  CAS  Google Scholar 

  34. Wohlfert, E.A., Callahan, M.K. & Clark, R.B. Resistance to CD4+CD25+ regulatory T cells and TGF-β in Cbl-b−/− mice. J. Immunol. 173, 1059–1065 (2004).

    Article  CAS  Google Scholar 

  35. King, C.G. et al. TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis. Nat. Immunol. 12, 1088–1092 (2006).

    CAS  Google Scholar 

  36. Liou, H.C. & Smith, K.A. The roles of c-rel and interleukin-2 in tolerance: a molecular explanation of self-nonself discrimination. Immunol. Cell Biol. 89, 27–32 (2011).

    Article  CAS  Google Scholar 

  37. Chen, E. et al. Degradation of proto-oncoprotein c-Rel by the ubiquitin-proteasome pathway. J. Biol. Chem. 273, 35201–35207 (1998).

    Article  CAS  Google Scholar 

  38. Lim, K.L. et al. Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation. J. Neurosci. 25, 2002–2009 (2005).

    Article  CAS  Google Scholar 

  39. Kumar, K.G. et al. Site-specific ubiquitination exposes a linear motif to promote interferon-α receptor endocytosis. J. Cell Biol. 179, 935–950 (2007).

    Article  CAS  Google Scholar 

  40. Varfolomeev, E. et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131, 669–681 (2007).

    Article  CAS  Google Scholar 

  41. Bertrand, M.J. et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. Cell 30, 689–700 (2008).

    Article  CAS  Google Scholar 

  42. Bryan, R.G. et al. Effect of CD28 signal transduction on c-Rel in human peripheral blood T cells. Mol. Cell Biol. 14, 7933–7942 (1994).

    Article  CAS  Google Scholar 

  43. Shapiro, V.S., Truitt, K.E., Imboden, J.B. & Weiss, A. CD28 mediates transcriptional upregulation of the interleukin-2 (IL-2) promoter through a composite element containing the CD28RE and NF-IL-2B AP-1 sites. Mol. Cell Biol. 17, 4051–4058 (1997).

    Article  CAS  Google Scholar 

  44. Chang, M., Lee, A.J., Fitzpatrick, L., Zhang, M. & Sun, S.C. NF-κB1 p105 regulates T cell homeostasis and prevents chronic inflammation. J. Immunol. 182, 3131–3138 (2009).

    Article  CAS  Google Scholar 

  45. Lee, Y.S. et al. Smad7 and Smad6 bind to discrete regions of Pellino-1 via their MH2 domains to mediate TGF-β1-induced negative regulation of IL-1R/TLR signaling. Biochem. Biophys. Res. Commun. 393, 836–843 (2010).

    Article  CAS  Google Scholar 

  46. Xiao, G., Harhaj, E.W. & Sun, S.C. NF-κB-inducing kinase regulates the processing of NF-κB2 p100. Mol. Cell 7, 401–409 (2001).

    Article  CAS  Google Scholar 

  47. Jin, W., Zhou, X.F., Yu, J., Cheng, X. & Sun, S.C. Regulation of Th17 cell differentiation and EAE induction by the MAP3K NIK. Blood 113, 6603–6610 (2009).

    Article  CAS  Google Scholar 

  48. Reiley, W.W. et al. Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J. Exp. Med. 204, 1475–1485 (2007).

    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. Reiley, W.W. et al. Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat. Immunol. 7, 411–417 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Texas Institute for Genomic Medicine for Peli1−/− mice; S.H. Park (Sungkyunkwan University) for hemagglutinin-tagged Peli1 and Peli1ΔC expression vectors; R. Beyaert (Ghent University) for E-tag–Peli1; X. Qin (MD Anderson Cancer Center) for lentiviral packaging vectors; Z. Chen (University of Texas Southwestern Medical Center) for the hemagglutinin-tagged K48R and K63R ubiquitin mutants; and K. Dwyer, K. Ramirez and K. Ackin from the flow cytometry core facility and S. Mudd from the histology core facility of MD Anderson Cancer Center for technical assistance. Supported by the US National Institutes of Health (AI057555, AI064639, GM84459 and GM84459-S1 to S.-C.S. and T32CA009598 to G.C.B).

Author information

Author notes

  1. Wei Jin

    Present address: Present address: Howard Hughes Medical Institute and Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.,

  2. Mikyoung Chang and Wei Jin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Mikyoung Chang, Wei Jin, Jae-Hoon Chang, Yichuan Xiao, George C Brittain, Jiayi Yu, Xiaofei Zhou, Yi-Hong Wang, Xuhong Cheng & Shao-Cong Sun

  2. Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA

    Pingwei Li

  3. Immunology Laboratory of Physician Scientists, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Brian A Rabinovich

  4. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Patrick Hwu

Authors
  1. Mikyoung Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jae-Hoon Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yichuan Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. George C Brittain
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiayi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaofei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yi-Hong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xuhong Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pingwei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Brian A Rabinovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Patrick Hwu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shao-Cong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.C. and W.J. designed and did the research and prepared the figures; J.-H.C. did the in vitro Treg cell assays and OVA tolerance assays; Y.X., J.Y. and X.Z. did the EAE experiment; G.C.B. did the experiments with knockdown and overexpression of Peli1 in EL4 cells; Y.-H.W. did the histology and immunohistochemistry; X.C. constructed Peli1 expression vectors; P.L., B.A.R. and P.H. contributed reagents; and S.-C.S. designed the research and wrote the manuscript.

Corresponding author

Correspondence to Shao-Cong Sun.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12 and Methods (PDF 8275 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chang, M., Jin, W., Chang, JH. et al. The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity. Nat Immunol 12, 1002–1009 (2011). https://doi.org/10.1038/ni.2090

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2090

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