Article

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

Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2004; 279(16):15870-6. DOI: 10.1074/jbc.M310599200
Source: PubMed

ABSTRACT 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.

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    • "Early studies have shown that PKCθ recruitment to the IS is indirectly dependent on the PI3K interaction motif within the CD28 cytosolic tail (Harada et al., 2001). Thus, mutation of Met 173 within the mouse YMNM motif, which binds PI3K upon its tyrosine phosphorylation, resulted in decreased ability of CD28 to direct PKCθ recruitment to the cSMAC, and inhibited PKCθ-dependent activation of NF-κB to and the Il2 gene (Sanchez-Lockhart et al., 2004). "
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    • "The antigen-induced signaling pathways for T cell activation through the T cell receptor (TCR) and co-stimulatory molecule CD28 have been extensively characterized. The binding of antigen peptide on MHC induces the clustering of a receptor complex that includes several tyrosine phosphorylated proteins , which recruits downstream signaling molecules including PKCh, CARMA1, Bcl10, and MALT1 to stimulate the activation of IKK [11] [12] [13] [14] [15]. In addition, the clustering of TCR results in the activation of all of the three MAPK pathways (ERK, JNK, p38) leading to AP-1, which have been identified as critical pathways regulating IL-2 production [16–21]. "
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    FEBS Letters 01/2006; 579(29):6641-6. DOI:10.1016/j.febslet.2005.10.059 · 3.34 Impact Factor
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    • "Although Ser565 does not fall into a putative PKC phosphorylation site, we also generated S565A mutant of CARMA1 and found that this mutant is also defective for TCR-induced NF-kB activation (Table 1), which further suggests the importance of this region for CARMA1's function. Previous studies indicate that CARMA1 recruits downstream signaling components such as Bcl10, IKK, and MALT1 into lipid rafts after CD3-CD28 costimulation (Che et al., 2004; Gaide et al., 2002; Hara et al., 2004; Figure 3. CARMA3, but Not CARMA2, Can Rescue TCR-Induced NF-kB Activation in CARMA1-Deficient Jurkat T Cells (A) Structural domain of CARMA family members. (B) Sequence aliments of the Linker region of CARMA1, CARMA2, and CARMA3. "
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