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J. Biol. Chem., Vol. 279, Issue 16, 15870-15876, April 16, 2004

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MALT1/Paracaspase Is a Signaling Component Downstream of CARMA1 and Mediates T Cell Receptor-induced NF-B Activation^*

Tuanjie Che, Yun You, Donghai Wang, Matthew J. Tanner, Vishva M. Dixit, and Xin Lin¶

From the Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214 and the Department of Molecular Oncology, Genentech Incorporated, South San Francisco, California 94080

T cell receptor (TCR) induces a series of signaling cascades and leads to activation of multiple transcription factors, including NF-B. Although the mechanism of TCR-induced NF-B activation is not fully understood, recent studies indicate that Bcl10 and CARMA1, two adaptor/scaffold proteins, play essential roles in mediating TCR-induced NF-B activation. MALT1/paracaspase is a caspase-like protein that contains an N-terminal death domain, two Ig-like domains, and a C-terminal caspase-like domain. It binds to Bcl10 through its Ig-like domains and cooperates with Bcl10 to activate NF-B. Recently, it has been shown that MALT1 is involved in mediating TCR signal transduction, leading to activation of NF-B. In this study, we show that MALT1 is recruited into the lipid rafts of the immunological synapse following activation of the TCR and the CD28 coreceptor (CD3/CD28 costimulation). This recruitment of MALT1 is dependent on CARMA1 because CD3/CD28 costimulation failed to recruit MALT1 into lipid rafts in CARMA1-deficient T cells. In addition, we also found that MALT1 not only binds to Bcl10 directly, but also associates with CARMA1 in a Bcl10-independent manner. Therefore, MALT1, Bcl10, and CARMA1 form a trimolecular complex. Expression of a MALT1 deletion mutant containing only the N-terminal death domain and the two Ig-like domains completely blocked CD3/CD28 costimulation-induced, but not tumor necrosis factor--induced, NF-B activation. Together, these results indicate that MALT1 is a crucial signaling component in the TCR signaling pathway.

Received for publication, September 25, 2003 , and in revised form, January 7, 2004.

^* This work was supported in part by National Institutes of Health Grants AI50848 and GM65899 (to X. L.) and by the Buswell Fellowship from the University at Buffalo, State University of New York (to Y. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Microbiology and Immunology, University at Buffalo, SUNY, 138 Farber Hall, 3435 Main St., Buffalo, NY 14214. Tel.: 716-829-3284; Fax: 716-829-2158; E-mail: xinlin{at}buffalo.edu.

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