NOD2

Gene Number: 64127

Location: 16q12.1

Key Functions: Bacterial recognition, innate immune activation, inflammation regulation, gut immune defense

NOD2 encodes nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular pattern recognition receptor (PRR) that plays a critical role in the innate immune system’s detection of bacterial pathogens. NOD2 is primarily expressed in monocytes, macrophages, dendritic cells, and intestinal epithelial cells, where it serves as a cytosolic sensor of muramyl dipeptide (MDP)—a conserved structural motif derived from bacterial peptidoglycan. By detecting this molecular signature, NOD2 acts as a sentinel for microbial invasion, triggering signaling cascades that promote immune activation and inflammation in defense of mucosal barriers, particularly within the gastrointestinal tract.

Upon recognition of MDP, NOD2 undergoes ATP-dependent oligomerization and recruits the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) via its caspase activation and recruitment domains (CARDs). This interaction initiates a downstream signaling cascade culminating in the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. The resulting transcriptional response induces the production of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), antimicrobial peptides such as defensins, and other effectors necessary for pathogen clearance and intestinal immune homeostasis.

NOD2 mutations have been associated with Blau syndrome (a rare granulomatous autoinflammatory disorder) and early-onset sarcoidosis, where gain-of-function mutations cause excessive NOD2 activation and spontaneous inflammation. This duality underscores the receptor’s tightly regulated role—both insufficient and excessive NOD2 signaling can drive pathology depending on genetic and environmental context.