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:

A requirement for CARMA1 in TCR-induced NF-κB activation

Nature Immunology volume 3, pages 830–835 (2002)Cite this article

Abstract

Stimulation of the T cell receptor (TCR) complex initiates multiple signaling cascades that lead to the activation of several transcription factors, including the NF-κB family members. Although various proximal signaling components of the TCR have been intensively studied, the distal components that mediate TCR-induced NF-κB activation remain largely unknown. Using a somatic mutagenesis approach, we cloned a CARMA1-deficient T cell line. Deficiency in CARMA1 (originally known as CARDII) resulted in selectively impaired activation of NF-κB induced by the TCR and a consequent defect in interleukin-2 (IL-2) production. Reconstitution of the CARMA1-deficient cells with CARMA1 fully rescued this signaling defect. Together, our results show that CARMA1 is an essential signaling component that mediates TCR-induced NF-κB activation.

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: Expression of an NF-κB–dependent EGFP gene in a mutant Jurkat T cell line.
Figure 2: NF-κB activation in JPM50.
Figure 3: Location of specific mutation(s) in JPM50.6 cells.
Figure 4: Proximal signaling pathways of CD3 and CD28 in JPM50.6 cells.
Figure 5: Expression of CARMA1 in JPM50.6 cells.
Figure 6: CARMA1 and expression of the gene encoding IL-2.
Figure 7: CARMA1 recruits Bcl10 to cytoplasmic membrane.

Similar content being viewed by others

References

  1. Weiss, A. & Littman, D.R. Signal transduction by lymphocyte antigen receptors. Cell 76, 263–274 (1994).

    Article  CAS  Google Scholar 

  2. Clements, J.L., Boerth, N.J., Lee, J.R. & Koretzky, G.A. Integration of T cell receptor-dependent signaling pathways by adapter proteins. Annu. Rev. Immunol. 17, 89–108 (1999).

    Article  CAS  Google Scholar 

  3. Zhang, W. & Samelson, L.E. The role of membrane-associated adaptors in T cell receptor signalling. Semin. Immunol. 12, 35–41 (2000).

    Article  CAS  Google Scholar 

  4. Rudd, C.E. Adaptors and molecular scaffolds in immune cell signaling. Cell 96, 5–8 (1999).

    Article  CAS  Google Scholar 

  5. Baldwin, A.J. The NF-κB and IκB proteins: new discoveries and insights. Annu. Rev. Immunol. 14, 649–683 (1996)

    Article  CAS  Google Scholar 

  6. Ghosh, S., May, M.J. & Kopp, E.B. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16, 225–260 (1998).

    Article  CAS  PubMed Central  Google Scholar 

  7. Verma, I.M., Stevenson, J.K., Schwarz, E.M., Van, A.D. & Miyamoto, S. Rel/NF-κB/IκB family: intimate tales of association and dissociation. Genes Dev. 9, 2723–2735 (1995).

    Article  CAS  PubMed Central  Google Scholar 

  8. Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621–663 (2000).

    Article  CAS  PubMed Central  Google Scholar 

  9. Chambers, C.A. & Allison, J.P. Costimulatory regulation of T cell function. Curr. Opin. Cell Biol. 11, 203–210 (1999).

    Article  CAS  Google Scholar 

  10. Monks, C.R., Kupfer, H., Tamir, I., Barlow, A. & Kupfer, A. Selective modulation of protein kinase C-θ during T-cell activation. Nature 385, 83–86 (1997).

    Article  CAS  Google Scholar 

  11. Coudronniere, N., Villalba, M., Englund, N. & Altman, A. NF-κB activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-θ. Proc. Natl. Acad. Sci. USA 97, 3394–3399 (2000).

    CAS  PubMed  Google Scholar 

  12. Lin, X., O'Mahony, A., Mu, Y., Geleziunas, R. & Greene, W.C. Protein kinase C-θ participates in NF-κB activation induced by CD3-CD28 costimulation through selective activation of IκB kinase β. Mol. Cell. Biol. 20, 2933–2940 (2000).

    Article  CAS  PubMed Central  Google Scholar 

  13. Sun, Z. et al. PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404, 402–407 (2000).

    Article  CAS  Google Scholar 

  14. Bi, K. et al. Antigen-induced translocation of PKC-θ to membrane rafts is required for T cell activation. Nature Immunol. 2, 556–563 (2001).

    Article  CAS  Google Scholar 

  15. Koseki, T. et al. CIPER, a novel NF-κB-activating protein containing a caspase recruitment domain with homology to Herpesvirus-2 protein E10. J. Biol. Chem. 274, 9955–9961 (1999).

    Article  CAS  Google Scholar 

  16. Srinivasula, S. et al. CLAP, a novel caspase recruitment domain-containing protein in the tumor necrosis factor receptor pathway, regulates NF-κB activation and apoptosis. J. Biol. Chem. 274, 17946–17954 (1999).

    Article  CAS  Google Scholar 

  17. Thome, M. et al. Equine herpesvirus-2 E10 gene product, but not its cellular homologue, activates NF-κB transcription factor and c-Jun N-terminal kinase. J. Biol. Chem. 274, 9962–9968 (1999).

    Article  CAS  Google Scholar 

  18. Willis, T.G. et al. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 96, 35–45 (1999).

    Article  CAS  Google Scholar 

  19. Yan, M., Lee, J., Schilbach, S., Goddard, A. & Dixit, V. mE10, a novel caspase recruitment domain-containing proapoptotic molecule. J. Biol. Chem. 274, 10287–10292 (1999).

    Article  CAS  Google Scholar 

  20. Zhang, Q. et al. Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32). Nature Genet. 22, 63–68 (1999).

    Article  CAS  Google Scholar 

  21. Ruland, J. et al. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104, 33–42 (2001).

    Article  CAS  Google Scholar 

  22. Bertin, J. et al. CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-κB. J. Biol. Chem. 275, 41082–41086 (2000).

    Article  CAS  Google Scholar 

  23. Bertin, J. et al. CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-κB. J. Biol. Chem. 276, 11877–11882 (2001).

    Article  CAS  Google Scholar 

  24. Gaide, O. et al. Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-κB activation. FEBS Lett. 496, 121–127 (2001).

    Article  CAS  Google Scholar 

  25. McAllister-Lucas, L. et al. Bimp1, a MAGUK family member linking protein kinase C activation to Bcl10-mediated NF-κB induction. J. Biol. Chem. 276, 30589–30597 (2001).

    Article  CAS  Google Scholar 

  26. Wang, L. et al. Card10 is a novel caspase recruitment domain/membrane-associated guanylate kinase family member that interacts with BCL10 and activates NF-κB. J. Biol. Chem. 276, 21405–21409 (2001).

    Article  CAS  Google Scholar 

  27. Dimitratos, S.D., Woods, D.F., Stathakis, D.G. & Bryant, P.J. Signaling pathways are focused at specialized regions of the plasma membrane by scaffolding proteins of the MAGUK family. BioEssays 21, 912–921 (1999).

    Article  CAS  Google Scholar 

  28. McKendry, R. et al. High-frequency mutagenesis of human cells and characterization of a mutant unresponsive to both α and γ interferons. Proc. Natl. Acad. Sci. USA 88, 11455–11459 (1991).

    Article  CAS  Google Scholar 

  29. Ting, A.T., Pimentel, M.F. & Seed, B. RIP mediates tumor necrosis factor receptor 1 activation of NF-κB but not Fas/APO-1-initiated apoptosis. EMBO J. 15, 6189–6196 (1996).

    Article  CAS  PubMed Central  Google Scholar 

  30. Lucas, P.C. et al. Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-κB signaling pathway. J. Biol. Chem. 276, 19012–19019 (2001).

    Article  CAS  Google Scholar 

  31. Uren, A.G. et al. Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol. Cell 6, 961–967 (2000).

    CAS  PubMed  Google Scholar 

  32. De Smaele, E. et al. Induction of GADD45β by NF-κB downregulates pro-apoptotic JNK signaling. Nature 414, 308–313 (2001).

    Article  CAS  Google Scholar 

  33. Tang, G. et al. Inhibition of JNK activation through NF-κB target genes. Nature 414, 313–317 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank V. Dixit, W. Greene, S.-C. Sun, J. Tschop, M. Yan and A. Weiss for reagents; M. Lindermann and S. Gaffen for help in the HT-2 cell proliferation assays; and J. Hay and S. Gaffen for critical reading of this manuscript.

Author information

Author notes

  1. Donghai Wang and Yun You: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology, School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, 14214, NY, USA

    Donghai Wang, Yun You, Sara M. Case & Xin Lin

  2. Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, 48109, MI, USA

    Linda M. McAllister-Lucas & Gabriel Nuñez

  3. Millennium Pharmaceuticals, Inc., Cambridge, 02139, MA, USA

    Lin Wang, Peter S. DiStefano & John Bertin

Authors
  1. Donghai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun You
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara M. Case
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Linda M. McAllister-Lucas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter S. DiStefano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gabriel Nuñez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John Bertin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xin Lin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, D., You, Y., Case, S. et al. A requirement for CARMA1 in TCR-induced NF-κB activation. Nat Immunol 3, 830–835 (2002). https://doi.org/10.1038/ni824

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni824

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