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CD3/CD28 Costimulation-Induced NF-B Activation Is Mediated by Recruitment of Protein Kinase C-, Bcl10, and IB Kinase ß to the Immunological Synapse through CARMA1

Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences,¹ Department of Oral Biology, School of Dental Medicine, University at Buffalo, SUNY, Buffalo, New York 14214,³ Department of Immunology, Sun Yet-Sen Medical School, Sun Yet-Sen University, Guangzhou 510089, People’s Republic of China²

Received 3 July 2003/ Returned for modification 12 August 2003/ Accepted 6 October 2003

CARMA1 (also known as CARD11) is a scaffold molecule and contains a caspase-recruitment domain (CARD) and a membrane-associated guanylate kinase-like (MAGUK) domain. It plays an essential role in mediating CD3/CD28 costimulation-induced NF-B activation. However, the molecular mechanism by which CARMA1 mediates costimulatory signals remains to be determined. Here, we show that CARMA1 is constitutively associated with the cytoplasmic membrane. This membrane association is essential for the function of CARMA1, since a mutant of CARMA1, CARMA1(L808P), that is defective in the membrane association cannot rescue CD3/CD28 costimulation-induced NF-B activation in JPM50.6 CARMA1-deficient T cells. Although CD3/CD28 costimulation effectively induces the formation of the immunological synapse in CARMA1-deficient T cells, the recruitment of protein kinase C- (PKC-), Bcl10, and IB kinase ß (IKKß) into lipid rafts of the immunological synapse is defective. Moreover, expression of wild-type CARMA1, but not CARMA1(L808P), restores the recruitment of PKC-, Bcl10, and IKKß into lipid rafts in CARMA1-deficient T cells. Consistently, expression of a mutant CARMA1, CARMA1(CD), that cannot associate with Bcl10 failed to restore CD3/CD28 costimulation-induced NF-B activation in JPM50.6 cells, whereas expression of Bcl10-CARMA(CD) fusion protein effectively restored this NF-B activation. Together, these results indicate that CARMA1 mediates CD3/CD28 costimulation-induced NF-B activation by recruiting downstream signaling components into the immunological synapse.

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