Abstract
The paracaspase MALT1 mediates T cell antigen receptor–induced signaling to the transcription factor NF-κB and is indispensable for T cell activation and proliferation. Enhanced expression of MALT1 or aberrant expression of a fusion protein of the apoptosis inhibitor API2 and MALT1 has been linked to mucosa-associated lymphoid tissue lymphoma. Despite the presence of a caspase-like domain, MALT1 proteolytic activity has not yet been demonstrated. Here we show that T cell antigen receptor stimulation induced recruitment of the NF-κB inhibitor A20 into a complex of MALT1 and the adaptor protein Bcl-10, leading to MALT1-mediated processing of A20. API2-MALT1 expression likewise resulted in cleavage of A20. MALT1 cleaved human A20 after arginine 439 and impaired its NF-κB-inhibitory function. Our studies identify A20 as a substrate of MALT1 and emphasize the importance of MALT1 proteolytic activity in the 'fine tuning' of T cell antigen receptor signaling.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Matsumoto, R. et al. Phosphorylation of CARMA1 plays a critical role in T cell receptor-mediated NF-κB activation. Immunity 23, 575–585 (2005).
Sommer, K. et al. Phosphorylation of the CARMA1 linker controls NF-κB activation. Immunity 23, 561–574 (2005).
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).
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).
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).
Ferch, U. et al. MALT1 directs B cell receptor-induced canonical nuclear factor-κB signaling selectively to the c-Rel subunit. Nat. Immunol. 8, 984–991 (2007).
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). Nat. Genet. 22, 63–68 (1999).
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).
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).
Sanchez-Izquierdo, D. et al. MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma. Blood 101, 4539–4546 (2003).
Zhou, H. et al. Bcl10 activates the NF-κB pathway through ubiquitination of NEMO. Nature 427, 167–171 (2004).
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).
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).
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).
Beyaert, R., Heyninck, K. & Van Huffel, S. A20 and A20-binding proteins as cellular inhibitors of nuclear factor-κB-dependent gene expression and apoptosis. Biochem. Pharmacol. 60, 1143–1151 (2000).
Lee, E.G. et al. Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice. Science 289, 2350–2354 (2000).
Tewari, M. et al. Lymphoid expression and regulation of A20, an inhibitor of programmed cell death. J. Immunol. 154, 1699–1706 (1995).
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).
Wang, D. et al. A requirement for CARMA1 in TCR-induced NF-κB activation. Nat. Immunol. 3, 830–835 (2002).
Su, T.T. et al. PKC-β controls IκB kinase lipid raft recruitment and activation in response to BCR signaling. Nat. Immunol. 3, 780–786 (2002).
Egawa, T. et al. Requirement for CARMA1 in antigen receptor-induced NF-κB activation and lymphocyte proliferation. Curr. Biol. 13, 1252–1258 (2003).
Snipas, S.J. et al. Characteristics of the caspase-like catalytic domain of human paracaspase. Biol. Chem. 385, 1093–1098 (2004).
Earnshaw, W.C., Martins, L.M. & Kaufmann, S.H. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem. 68, 383–424 (1999).
Vercammen, D. et al. Type II metacaspases Atmc4 and Atmc9 of Arabidopsis thaliana cleave substrates after arginine and lysine. J. Biol. Chem. 279, 45329–45336 (2004).
Wertz, I.E. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature 430, 694–699 (2004).
Boone, D.L. et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat. Immunol. 5, 1052–1060 (2004).
Boatright, K.M. et al. A unified model for apical caspase activation. Mol. Cell 11, 529–541 (2003).
Heyninck, K. & Beyaert, R. A20 inhibits NF-κB activation by dual ubiquitin-editing functions. Trends Biochem. Sci. 30, 1–4 (2005).
Mauro, C. et al. ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-κB. J. Biol. Chem. 281, 18482–18488 (2006).
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).
Dykstra, M., Cherukuri, A., Sohn, H.W., Tzeng, S.J. & Pierce, S.K. Location is everything: lipid rafts and immune cell signalling. Annu. Rev. Immunol. 21, 457–481 (2003).
Gaide, O. et al. CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-κB activation. Nat. Immunol. 3, 836–843 (2002).
Misra, R.S. et al. Caspase-8 and c-FLIPL associate in lipid rafts with NF-κB adaptors during T cell activation. J. Biol. Chem. 282, 19365–19374 (2007).
Noels, H. et al. A novel TRAF6 binding site in MALT1 defines distinct mechanisms of NF-κB activation by API2MALT1 fusions. J. Biol. Chem. 282, 10180–10189 (2007).
McAllister-Lucas, L.M. et al. CARMA3/Bcl10/MALT1-dependent NF-κB activation mediates angiotensin II-responsive inflammatory signalling in nonimmune cells. Proc. Natl. Acad. Sci. USA 104, 139–144 (2007).
Klemm, S., Zimmermann, S., Peschel, C., Mak, T.W. & Ruland, J. Bcl10 and Malt1 control lysophosphatidic acid-induced NF-κB activation and cytokine production. Proc. Natl Acad. Sci. USA 104, 134–138 (2007).
Klemm, S. et al. The Bcl10-Malt1 complex segregates FcεRI-mediated nuclear factor κB activation and cytokine production from mast cell degranulation. J. Exp. Med. 203, 337–347 (2006).
Gross, O. et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651–656 (2006).
Heyninck, K. et al. The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-κB-inhibiting protein ABIN. J. Cell Biol. 145, 1471–1482 (1999).
Acknowledgements
We thank D. Vlieghe and P. Hulpiau for help with the alignment of caspase-like molecules; J. Phillipe (Ghent University, Belgium) and M. Dyer (University of Leicester, UK) for gifts of the Jurkat and SSK41 cell lines, respectively; and S. Janssens and D. Vercammen for discussions. Supported by the 'Interuniversity Attraction Poles' (IAP6/18 to R.B. and IAP5/25 to P.M.), 'Fonds voor Wetenschappelijk Onderzoek-Vlaanderen' (3G010505 to R.B. and G050704 to P.M.), King Baudouin Foundation (Alphonse and Jean Forton Fund; R.B.), Ghent University (Concerted Action Grant 01G06B6 to R.B.) and Catholic University Leuven (Concerted Action Grant to P.M.).
Author information
Authors and Affiliations
Contributions
B.C., M.B., K.H., T.B., M.H. and J.S. did the experiments; L.S. and Z.J.C. provided recombinant MALT1; B.C., M.B. and R.B. wrote the paper; B.C., M.B., K.H. and R.B. designed the experiments; and R.B. and P.M. supervised the experiments, offered scientific advice and share senior authorship.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–6 (PDF 728 kb)
Rights and permissions
About this article
Cite this article
Coornaert, B., Baens, M., Heyninck, K. et al. T cell antigen receptor stimulation induces MALT1 paracaspase–mediated cleavage of the NF-κB inhibitor A20. Nat Immunol 9, 263–271 (2008). https://doi.org/10.1038/ni1561
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni1561
This article is cited by
-
Targeting tumor exosomal circular RNA cSERPINE2 suppresses breast cancer progression by modulating MALT1-NF-𝜅B-IL-6 axis of tumor-associated macrophages
Journal of Experimental & Clinical Cancer Research (2023)
-
MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas
Blood Cancer Journal (2023)
-
Pharmacological inhibition of MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) induces ferroptosis in vascular smooth muscle cells
Cell Death Discovery (2023)
-
Airway epithelial immunoproteasome subunit LMP7 protects against rhinovirus infection
Scientific Reports (2022)
-
A20 and ABIN-1 cooperate in balancing CBM complex-triggered NF-κB signaling in activated T cells
Cellular and Molecular Life Sciences (2022)