Antigen-independent signalosome of CARMA1, PKCθ, and TNF receptor-associated factor 2 (TRAF2) determines NF-κB signaling in T cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 7; pp. 2903 - 2908
• Main Authors: So, Takanori, Soroosh, Pejman, Eun, So-Young, Altman, Amnon, Croft, Michael, Grey, Howard M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15.02.2011; National Acad Sciences
• Subjects: Animals; Antigens; Biological Sciences; Blotting, Western; CARD Signaling Adaptor Proteins - immunology; CARD Signaling Adaptor Proteins - metabolism; Cultured cells; Fluorescent Antibody Technique; Hybridomas; Immunity; Immunoprecipitation; Isoenzymes - immunology; Isoenzymes - metabolism; Mice; Molecules; Multiprotein Complexes - immunology; Multiprotein Complexes - metabolism; NF-kappa B - metabolism; Phosphorylation; Protein Kinase C - immunology; Protein Kinase C - metabolism; Protein Kinase C-theta; Receptors; Receptors, OX40 - immunology; Receptors, OX40 - metabolism; Signal Transduction - immunology; T cell antigen receptors; T lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; TNF Receptor-Associated Factor 2 - immunology; TNF Receptor-Associated Factor 2 - metabolism; Tumor necrosis factor receptors; Ultracentrifugation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1008765108

NF-κB activation is essential for T-cell responses, and costimulatory molecules in the TNF receptor (TNFR) superfamily are viewed as a major source of this signal. Although the TNFR family recruits TNFR-associated factor (TRAF) molecules leading to IKKα/β/γ activation, it is not clear whether simple binding of TRAFs explains why they are such strong activators of NF-κB and so important for T-cell immunity. We now show that one TNFR family member, OX40 (CD134), after ligation by OX40L, assembles a unique complex that not only contains TRAF2, RIP, and IKKα/β/γ but also CARMA1, MALT1, BCL10, and PKCO, molecules previously shown to regulate NF-KB activation through the T-cell receptor (TCR). The OX40 signalosome is formed in membrane microdomains irrespective of TCR engagement, and strongly promotes NF-κB activation only if CARMA1 and PKC6 are recruited. This NF-κB signal allows effector/memory T cells to survive when antigen is no longer available. Thus, by recruiting TCR-related intracellular molecules into the TRAF2 complex, OX40 provides the T cell with a high level of NF-κB activity needed for longevity.