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

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 IKK gamma and was inhibited by dominant negative mutants of I kappaB alpha, IKK alpha, IKK beta, and IKK gamma. Nod2 interacted with the serine-threonine kinase RICK via a hemophilic 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.