title: MALT1/paracaspase is a signaling component downstream of CARMA1 and mediates T cell receptor-induced NF-kappaB activation.
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.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214, USA.
authors.forename: Tuanjie
authors.initials: T
authors.lastname: Che
authors.forename: Yun
authors.initials: Y
authors.lastname: You
authors.forename: Donghai
authors.initials: D
authors.lastname: Wang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Tanner
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
mesh_terms: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D020169:Caspases; D006162:Guanylate Cyclase / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D018442:Lymphoma, B-Cell, Marginal Zone; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D009363:Neoplasm Proteins; D011506:Proteins / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426242:CARD11 protein, human; D006162:Guanylate Cyclase