NODs: intracellular proteins involved in inflammation and apoptosis

Abstract

The family of NOD proteins includes the apoptosis regulator APAF1 (apoptotic protease activating factor 1) and up to 25 NOD-LRR proteins, some of which have been implicated in the regulation of inflammatory responses. Most NOD proteins are comprised of three distinct functional domains: an amino-terminal effector-binding domain (EBD), a centrally located nucleotide-binding oligomerization domain (NOD) and a carboxy-terminal ligand-recognition domain (LRD). The EBD of NOD-family members is highly diverse but most NOD proteins contain caspase-recruitment domains (CARDs) or pyrin domains (PYDs). With the exception of APAF1, all mammalian NOD proteins contain leucine-rich repeats (LRRs) as LRDs. Two NOD proteins, NOD1 and NOD2, recognize bacterial components through their LRRs and mediate the activation of nuclear factor-κB (NF-κB) through the downstream effector RICK. NOD2 recognizes muramyl dipeptide, a conserved structure in bacterial peptidoglycan. Many NOD proteins, including APAF1, NOD1, NOD2, death effector filament-forming CED-4-like apoptosis protein (DEFCAP), ICE-protease activating factor (IPAF) and cryopyrin, have been shown to induce or enhance apoptosis. Several NOD proteins, including IPAF and cryopyrin, associate with ASC, an adaptor molecule containing a CARD and a PYD. Oligomerization of cryopyrin and IPAF mediates NF-κB and caspase activation through ASC. Genetic variation of three human NOD proteins — NOD2, cryopyrin and MHC class II transactivator (CIITA) — has been implicated in inflammatory disease and/or immunodeficiency. Genetic variation in neuronal apoptosis inhibitory protein (NAIP) has been shown to affect intracellular replication of Legionella pneumophila in mice.