Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB

Apaf-1 and NOD1 are members of a protein family, each of which contains a Caspase recruitment domain (CARD) linked to a nucleotide-binding domain, which regulate Apoptosis and/or NF-kappaB activation. NOD2, a third member of the family, was identified. NOD2 is composed of two N-terminal CARDs, a nucleotide-binding domain, and multiple C-terminal leucine-rich repeats. Although NOD1 and Apaf-1 were broadly expressed in tissues, the expression of NOD2 was highly restricted to monocytes. NOD2 induced nuclear factor kappaB (NF-kappaB) activation, which required IKKgamma and was inhibited by dominant negative mutants of IkappaBalpha, IKKalpha, IKKbeta, and IKKgamma. NOD2 interacted with the serine-threonine kinase RICK via a homophilic CARD-CARD interaction. Furthermore, NF-kappaB activity induced by NOD2 correlated with its ability to interact with RICK and was specifically inhibited by a truncated mutant form of RICK containing its CARD. The identification of NOD2 defines a subfamily of Apaf-1-like proteins that function through RICK to activate a NF-kappaB signaling pathway.