The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 enable detection of intracellular bacteria and promote their clearance through initiation of a pro-inflammatory transcriptional programme and other host defence pathways, including autophagy. The NOD1 and NOD2 proteins comprise a series of carboxyterminal leucine-rich repeats (LRRs), as well as a central nucleotide-binding domain (NBD; also known as a NOD domain), which contains NACHT, winged helix and superhelical subdomains. NOD1 (nucleotide-binding oligomerization domain-containing protein 1) contains a single amino-terminal caspase recruitment domain (CARD), and NOD2 contains tandem N-terminal CARDs that interact with the CARD of receptor-interacting protein 2 (RIP2).
 Both NOD1 and NOD2 contain a central nucleotide-binding domain (NBD), which binds ATP and mediates NOD oligomerization, and carboxy-terminal leucine-rich repeats (LRRs), which are important for ligand sensing.NOD1 and NOD2 are cytosolic proteins that respond to intracellular fragments of bacterial peptidoglycan and that initiate nuclear factor-κB (NF-κB)-dependent and mitogen-activated protein kinase (MAPK)-dependent gene transcription. NOD1 detects d-glutamylmeso-diaminopimelic acid (iE-DAP), which is a dipeptide that is present in a peptidoglycan that is primarily found in Gram-negative bacteria but also in select groups of Gram-positive bacteria. By contrast, NOD2 detects muramyl dipeptide (MDP) that is ubiquitously present in bacterial peptidoglycan. Both gain-of-function and loss-of-function mutations in NOD2 have been associated with human disease; loss-of-function mutations of NOD2 affecting NOD2-mediated peptidoglycan sensing are associated with Crohn’s disease, whereas gain-of-function mutations in the NBD of NOD2 correlate with the autoinflammatory diseases Blau syndrome and early-onset sarcoidosis, which suggests that a regulated level of NOD2 signalling is crucial.

References

1.Philpott DJ,et al. Nat Rev Immunol. 2014;14(1):9–23.