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Mol. Cell. Biol. doi:10.1128/MCB.00418-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

THE PKC-RESPONSIVE INHIBITORY DOMAIN OF CARD11 FUNCTIONS IN NF-B ACTIVATION TO REGULATE THE ASSOCIATION OF MULTIPLE SIGNALING COFACTORS THAT DIFFERENTIALLY DEPEND ON Bcl10 AND MALT1 FOR ASSOCIATION

Department of Biological Chemistry and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

^* To whom correspondence should be addressed. Email: joel.pomerantz{at}jhmi.edu.

	Abstract

The activation of NF-B by T cell receptor (TCR) signaling is critical for T cell activation during the adaptive immune response. CARD11 is a multi-domain adapter that is required for TCR signaling to the IKK complex. During TCR signaling, the region in CARD11 between the Coiled-coil and PDZ domains is phosphorylated by PKC in a required step in NF-B activation. In this report, we demonstrate that this region functions as an inhibitory domain (ID) that controls the association of CARD11 with multiple signaling cofactors, including Bcl10, TRAF6, TAK1, IKK, and Caspase-8, through an interaction that requires both the CARD and Coiled-coil domains. Consistent with the ID-mediated control of their association, we demonstrate that TRAF6 and Caspase-8 associate with CARD11 in T cells in a signal-inducible manner. Using an RNAi-rescue assay, we demonstrate that the CARD, Linker 1, Coiled-coil, Linker 3, SH3, Linker 4, and GUK domains are each required for TCR signaling to NF-B downstream of ID neutralization. Requirements for the CARD, Linker 1, and Coiled-coil domains in signaling are consistent with their roles in the association of CARD11 with Bcl10, TRAF6, TAK1, Caspase-8, and IKK. Using Bcl10- and MALT1-deficient cells, we show that CARD11 can recruit signaling cofactors independently of one another in a signal-inducible manner.