Nod2, a Nod1/Apaf-1 Family Member That Is Restricted to Monocytes and Activates NF-κB

TLDR

Apaf‑1 and Nod1 are CARD‑containing proteins that regulate apoptosis and NF‑κB, and the newly identified Nod2, a monocyte‑restricted member with two CARDs, a nucleotide‑binding domain, and leucine‑rich repeats, expands this family. Nod2 activates NF‑κB in monocytes through IKKγ and a CARD‑CARD interaction with the kinase RICK, and its activity depends on RICK, defining a subfamily of Apaf‑1‑like proteins that signal via RICK to NF‑κB.

Abstract

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-κB 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 κB (NF-κB) activation, which required IKKγ and was inhibited by dominant negative mutants of IκBα, IKKα, IKKβ, and IKKγ. Nod2 interacted with the serine-threonine kinase RICK via a homophilic CARD-CARD interaction. Furthermore, NF-κB 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-κB signaling pathway.