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Multifunctional roles for MALT1 in T-cell activation

Nature Reviews Immunology volume 8, pages 495–500 (2008)Cite this article

Abstract

The activation of T cells is vital to the successful elimination of pathogens, but can also have a deleterious role in autoimmunity and transplant rejection. Various signalling pathways are triggered by the T-cell receptor; these have key roles in the control of the T-cell response and represent interesting targets for therapeutic immunomodulation. Recent findings define MALT1 (mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1) as a protein with proteolytic activity that controls T-cell activation by regulating key molecules in T-cell-receptor-induced signalling pathways.

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Figure 1: Roles of MALT1 in receptor-induced NF-κB activation.
Figure 2: Structural and functional elements of MALT1.
Figure 3: Role of MALT1 in TCR-induced signalling pathways.

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References

  1. Ruland, J., Duncan, G. S., Wakeham, A. & Mak, T. W. Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 19, 749–758 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Ruefli-Brasse, A. A., French, D. M. & Dixit, V. M. Regulation of NF-κB-dependent lymphocyte activation and development by paracaspase. Science 302, 1581–1584 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Wegener, E. & Krappmann, D. CARD–Bcl10–Malt1 signalosomes: missing link to NF-κB. Sci. STKE 2007, pe21 (2007).

    Article  PubMed  Google Scholar 

  4. 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  PubMed  Google Scholar 

  5. 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 

  6. 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  PubMed  Google Scholar 

  7. Ferch, U. et al. MALT1 directs B cell receptor-induced canonical nuclear factor-κB signaling selectively to the c-Rel subunit. Nature Immunol. 8, 984–991 (2007).

    Article  CAS  Google Scholar 

  8. Akagi, T. et al. A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. Oncogene 18, 5785–5794 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Dierlamm, J. et al. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 93, 3601–3609 (1999).

    CAS  PubMed  Google Scholar 

  10. Morgan, J. A. et al. Breakpoints of the t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma lie within or near the previously undescribed gene MALT1 in chromosome 18. Cancer Res. 59, 6205–6213 (1999).

    CAS  PubMed  Google Scholar 

  11. Isaacson, P. G. & Du, M. Q. MALT lymphoma: from morphology to molecules. Nature Rev. Cancer 4, 644–653 (2004).

    Article  CAS  Google Scholar 

  12. Lucas, P. C., McAllister-Lucas, L. M. & Nunez, G. NF-κB signaling in lymphocytes: a new cast of characters. J. Cell. Sci. 117, 31–39 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Ngo, V. N. et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441, 106–110 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Jost, P., Peschel, C. & Ruland, J. The Bcl10/Malt1 signaling pathway as a drug target in lymphoma. Curr. Drug Targets 7, 1335–1340 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Thome, M. CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nature Rev. Immunol. 4, 348–359 (2004).

    Article  CAS  Google Scholar 

  16. Gross, O. et al. Multiple ITAM-coupled NK cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF-κB and MAPK activation to selectively control cytokine production. Blood 11 January 2008 (doi:10.1182/blood-2007-11-123513).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gross, O. et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651–656 (2006).

    CAS  PubMed  Google Scholar 

  18. Hara, H. et al. The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nature Immunol. 8, 619–629 (2007).

    Article  CAS  Google Scholar 

  19. Klemm, S. et al. The Bcl10–Malt1 complex segregates FcɛRI-mediated nuclear factor κB activation and cytokine production from mast cell degranulation. J. Exp. Med. 203, 337–347 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dong, W. et al. The IRAK-1–BCL10–MALT1–TRAF6–TAK1 cascade mediates signaling to NF-κB from Toll-like receptor 4. J. Biol. Chem. 281, 26029–26040 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Hsu, Y.-M. S. et al. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nature Immunol. 8, 198–205 (2007).

    Article  CAS  Google Scholar 

  22. 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 

  23. Rawlings, D. J., Sommer, K. & Moreno-García, M. E. The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nature Rev. Immunol. 6, 799–812 (2006).

    Article  CAS  Google Scholar 

  24. Hacker, H. & Karin, M. Regulation and function of IKK and IKK-related kinases. Sci STKE 2006, re13 (2006).

    Article  PubMed  Google Scholar 

  25. Zhou, H., Du, M. Q. & Dixit, V. M. Constitutive NF-κB activation by the t(11;18)(q21;q21) product in MALT lymphoma is linked to deregulated ubiquitin ligase activity. Cancer Cell 7, 425–431 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Che, T. et al. MALT1/paracaspase is a signaling component downstream of CARMA1 and mediates T cell receptor-induced NF-κB activation. J. Biol. Chem. 279, 15870–15876 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Sun, L., Deng, L., Ea, C. K., Xia, Z. P. & Chen, Z. J. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol. Cell 14, 289–301 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Noels, H. et al. A Novel TRAF6 binding site in MALT1 defines distinct mechanisms of NF-κB activation by API2–MALT1 fusions. J. Biol. Chem. 282, 10180–10189 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Yoneda, T. et al. Regulatory mechanisms of TRAF2-mediated signal transduction by Bcl10, a MALT lymphoma-associated protein. J. Biol. Chem. 275, 11114–11120 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Oeckinghaus, A. et al. Malt1 ubiquitination triggers NF-κB signaling upon T-cell activation. EMBO J. 26, 4634–4645 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wu, C. J. & Ashwell, J. D. NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-κB activation. Proc. Natl Acad. Sci. USA 105, 3023–3028 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stilo, R. et al. Physical and functional interaction of CARMA1 and CARMA3 with Iκkinaseγ–NFκB essential modulator. J. Biol. Chem. 279, 34323–34331 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Shambharkar, P. B. et al. Phosphorylation and ubiquitination of the IκB kinase complex by two distinct signaling pathways. EMBO J. 26, 1794–1805 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Snipas, S. J. et al. Characteristics of the caspase-like catalytic domain of human paracaspase. Biol. Chem. 385, 1093–1098 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Coornaert, B. et al. T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-κB inhibitor A20. Nature Immunol. 9, 263–271 (2008).

    Article  CAS  Google Scholar 

  36. Rebeaud, F. et al. The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nature Immunol. 9, 272–281 (2008).

    Article  CAS  Google Scholar 

  37. Vercammen, D., Declercq, W., Vandenabeele, P. & Van Breusegem, F. Are metacaspases caspases? J. Cell Biol. 179, 375–380 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Heyninck, K. & Beyaert, R. A20 inhibits NF-κB activation by dual ubiquitin-editing functions. Trends Bioch. Sci. 30, 1–4 (2005).

    Article  CAS  Google Scholar 

  39. Klinkenberg, M., Van Huffel, S., Heyninck, K. & Beyaert, R. Functional redundancy of the zinc fingers of A20 for inhibition of NF-κB activation and protein–protein interactions. FEBS Lett. 498, 93–97 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Kinashi, T. Intracellular signalling controlling integrin activation in lymphocytes. Nature Rev. Immunol. 5, 546–559 (2005).

    Article  CAS  Google Scholar 

  41. Lu, T. T. & Cyster, J. G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297, 409–412 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Rueda, D. et al. Bcl10 controls TCR- and FcγR-induced actin polymerization. J. Immunol. 178, 4373–4384 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Zhou, H. et al. Bcl10 activates the NF-κB pathway through ubiquitination of NEMO. Nature 427, 167–171 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I would like to thank members of my laboratory for critical comments on the manuscript. Our work is supported by grants from the Swiss National Science Foundation, the Swiss Cancer League and the Novartis and Vontobel Foundations.

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  1. Margot Thome is at the Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland. margot.thomemiazza@unil.ch,

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Thome, M. Multifunctional roles for MALT1 in T-cell activation. Nat Rev Immunol 8, 495–500 (2008). https://doi.org/10.1038/nri2338

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