Che Tuanjie, You Yun, Wang Donghai, Tanner Matthew J, Dixit Vishva M, Lin Xin
Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214, USA.
J Biol Chem. 2004 Apr 16;279(16):15870-6. doi: 10.1074/jbc.M310599200. Epub 2004 Jan 30.
T cell receptor (TCR) induces a series of signaling cascades and leads to activation of multiple transcription factors, including NF-kappaB. Although the mechanism of TCR-induced NF-kappaB activation is not fully understood, recent studies indicate that Bcl10 and CARMA1, two adaptor/scaffold proteins, play essential roles in mediating TCR-induced NF-kappaB 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-kappaB. Recently, it has been shown that MALT1 is involved in mediating TCR signal transduction, leading to activation of NF-kappaB. 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-alpha-induced, NF-kappaB activation. Together, these results indicate that MALT1 is a crucial signaling component in the TCR signaling pathway.
T细胞受体（TCR）诱导一系列信号级联反应，并导致包括核因子κB（NF-κB）在内的多种转录因子的激活。尽管TCR诱导NF-κB激活的机制尚未完全阐明，但最近的研究表明，两种接头/支架蛋白Bcl10和CARMA1在介导TCR诱导的NF-κB激活中发挥着重要作用。MALT1/副胱天蛋白酶是一种类胱天蛋白酶蛋白，其包含一个N端死亡结构域、两个免疫球蛋白样结构域和一个C端类胱天蛋白酶结构域。它通过其免疫球蛋白样结构域与Bcl10结合，并与Bcl10协同激活NF-κB。最近的研究表明，MALT1参与介导TCR信号转导，从而导致NF-κB的激活。在本研究中，我们发现TCR和CD28共受体（CD3/CD28共刺激）激活后，MALT1被招募到免疫突触的脂筏中。MALT1的这种招募依赖于CARMA1，因为在CARMA1缺陷的T细胞中，CD3/CD28共刺激无法将MALT1招募到脂筏中。此外，我们还发现MALT1不仅直接与Bcl10结合，还以不依赖Bcl10的方式与CARMA1相互作用。因此，MALT1、Bcl10和CARMA1形成了一个三分子复合物。仅包含N端死亡结构域和两个免疫球蛋白样结构域的MALT1缺失突变体的表达完全阻断了CD3/CD28共刺激诱导的NF-κB激活，但不影响肿瘤坏死因子-α诱导的NF-κB激活。综上所述，这些结果表明MALT1是TCR信号通路中的一个关键信号成分。
