CARD11 mediates factor-specific activation of NF-κB by the T cell receptor complex

NF-κB is a critical target of signaling downstream of the T cell receptor (TCR) complex, but how TCR signaling activates NF-κB is poorly understood. We have developed an expression cloning strategy that can identify catalytic and noncatalytic molecules that participate in different pathways of NF-κB activation. Screening of a mouse thymus cDNA library yielded CARD11, a membrane-associated guanylate kinase (MAGUK) family member containing CARD, PDZ, SH3 and GUK domains. Using a CARD-deleted variant of CARD11 and RNA interference (RNAi), we demonstrate that CARD11 mediates NF-κB activation by αCD3/αCD28 cross-linking and PMA/ionomycin treatment, but not by TNFα or dsRNA. CARD11 is not required for TCR-mediated induction of NFAT or AP-1. CARD11 functions upstream of the IκB-kinase (IKK) complex and cooperates with Bcl10 in a CARD domain-dependent manner. RNAi-rescue experiments suggest that the CARD, coiled-coil, SH3 and GUK domains of CARD11 are critical for its signaling function. These results implicate CARD11 in factor-specific activation of NF-κB by the TCR complex and establish a role for a MAGUK family member in antigen receptor signaling.