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

• Published in: The Journal of biological chemistry 2004-04, Vol.279 (16), p.15870-15876
• Main Authors: Che, Tuanjie, You, Yun, Wang, Donghai, Tanner, Matthew J., Dixit, Vishva M., Lin, Xin
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M310599200

T cell receptor (TCR) induces a series of signaling cascades and leads to activation of multiple transcription factors, including NF-κB. Although the mechanism of TCR-induced NF-κB activation is not fully understood, recent studies indicate that Bcl10 and CARMA1, two adaptor/scaffold proteins, play essential roles in mediating TCR-induced NF-κB 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-κB. Recently, it has been shown that MALT1 is involved in mediating TCR signal transduction, leading to activation of NF-κB. 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-α-induced, NF-κB activation. Together, these results indicate that MALT1 is a crucial signaling component in the TCR signaling pathway.