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’s activity contributes to immune regulation through several key functions:

1. Bacterial recognition and host defense:NOD2 acts as an intracellular sensor for bacterial cell wall components, complementing the extracellular detection performed by Toll-like receptors (TLRs). Its activation enhances local antimicrobial responses and strengthens epithelial barrier integrity.

   
   

2. Regulation of intestinal immune balance:In the gut, NOD2 modulates the cross-talk between the host and the commensal microbiota. It limits excessive immune activation by promoting tolerance to symbiotic bacteria while maintaining readiness to respond to pathogenic invasion.

   
   

3. Inflammation control and autophagy:NOD2 interacts with autophagy-related proteins such as ATG16L1, coordinating bacterial clearance via autophagosome formation. This function is essential for preventing chronic inflammation and maintaining mucosal equilibrium.

   
   

Genetic variants in NOD2 are among the most strongly established genetic risk factors for Crohn’s disease, a major form of inflammatory bowel disease (IBD). Three common loss-of-function variants—R702W (rs2066844), G908R (rs2066845), and 1007fs (Leu1007fsX1008, rs2066847)—impair the receptor’s ability to recognize MDP and activate downstream NF-κB signaling. This leads to defective bacterial sensing, diminished antimicrobial peptide production, and aberrant immune responses to intestinal microbiota. The resulting imbalance between host defense and microbial tolerance promotes chronic intestinal inflammation, tissue injury, and dysbiosis.

Beyond Crohn’s disease, 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.

In summary, NOD2 functions as a crucial intracellular immune receptor that links bacterial recognition to innate and adaptive immune activation. Its precise modulation is essential for maintaining intestinal immune homeostasis, protecting against infection while preventing unwarranted inflammation. Genetic dysregulation of NOD2 highlights its central role in mucosal immunity and its importance as a molecular bridge between microbial sensing, inflammation, and intestinal health.