Cutting edge: the "death" adaptor CRADD/RAIDD targets BCL10 and suppresses agonist-induced cytokine expression in T lymphocytes.

Lin Q, Liu Y, Moore DJ, Elizer SK, Veach RA, Hawiger J, Ruley HE
J Immunol. 2012 188 (6): 2493-7

PMID: 22323537 · PMCID: PMC3294148 · DOI:10.4049/jimmunol.1101502

The expression of proinflammatory cytokines and chemokines in response to TCR agonists is regulated by the caspase-recruitment domain membrane-associated guanylate kinase 1 (CARMA1) signalosome through the coordinated assembly of complexes containing the BCL10 adaptor protein. We describe a novel mechanism to negatively regulate the CARMA1 signalosome by the "death" adaptor protein caspase and receptor interacting protein adaptor with death domain (CRADD)/receptor interacting protein-associated ICH-1/CED-3 homologous protein with a death domain. We show that CRADD interacts with BCL10 through its caspase recruitment domain and suppresses interactions between BCL10 and CARMA1. TCR agonist-induced interaction between CRADD and BCL10 coincides with reduction of its complex formation with CARMA1 in wild-type, as compared with Cradd-deficient, primary cells. Finally, Cradd-deficient spleen cells, CD4(+) T cells, and mice respond to T cell agonists with strikingly higher production of proinflammatory mediators, including IFN-γ, IL-2, TNF-α, and IL-17. These results define a novel role for CRADD as a negative regulator of the CARMA1 signalosome and suppressor of Th1- and Th17-mediated inflammatory responses.

MeSH Terms (14)

Adaptor Proteins, Signal Transducing Animals B-Cell CLL-Lymphoma 10 Protein CARD Signaling Adaptor Proteins CD4-Positive T-Lymphocytes Cell Separation CRADD Signaling Adaptor Protein Flow Cytometry Immunoblotting Immunoprecipitation Lymphocyte Activation Mice Mice, Inbred C57BL Signal Transduction

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