NOD2 Gene: Structure, Function, and Clinical Significance
A comprehensive guide to the NOD2 gene, its role in innate immunity, associated diseases, and clinical implications.
Gene Information Card
| Symbol | NOD2 |
|---|---|
| Full Name | Nucleotide-binding oligomerization domain containing 2 |
| Gene Type | Protein coding |
| Chromosomal Location | 16q12.1 |
| NCBI Gene ID | 64127 ncbi.nlm.nih.gov/gene/64127 |
| Ensembl ID | ENSG00000167207 |
| UniProt ID | Q9HC29 |
| OMIM ID | 605956 |
| HGNC ID | HGNC:5331 |
| Aliases | CARD15, IBD1, BLAU, ACUG, CLR16.3, PSORAS1 |
Description
The NOD2 gene encodes the NOD2 protein, a critical intracellular pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments, particularly muramyl dipeptide (MDP). It plays a pivotal role in innate immune responses by activating NF-κB and MAPK signaling pathways, leading to the production of pro-inflammatory cytokines and antimicrobial peptides. NOD2 is expressed primarily in monocytes, macrophages, dendritic cells, and intestinal epithelial cells, where it contributes to mucosal defense and immune homeostasis. Mutations in NOD2 are strongly associated with susceptibility to Crohn's disease, Blau syndrome, and other inflammatory conditions.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Crohn's Disease | Loss-of-function mutations (e.g., R702W, G908R, 1007fs) impair MDP recognition and NF-κB activation, leading to defective bacterial clearance and dysregulated intestinal inflammation. | Multiple genome-wide association studies and functional assays (e.g., Ogura et al., 2001; Hugot et al., 2001). |
| Blau Syndrome | Gain-of-function mutations (e.g., R334W, R334Q, L469F) in the NACHT domain cause constitutive NF-κB activation, leading to granulomatous inflammation in skin, joints, and eyes. | Familial linkage and functional studies (e.g., Miceli-Richard et al., 2001). |
| Early-Onset Sarcoidosis | Similar gain-of-function mutations as Blau syndrome, presenting with granulomatous inflammation in early childhood. | Case reports and genetic testing (e.g., Kanazawa et al., 2005). |
| Graft-Versus-Host Disease | NOD2 variants in donors or recipients may influence inflammatory responses after allogeneic hematopoietic stem cell transplantation. | Association studies (e.g., Holler et al., 2004). |
| Lung Cancer | NOD2 polymorphisms may modulate immune surveillance and inflammation, affecting lung cancer risk and prognosis. | Case-control studies (e.g., Zhang et al., 2015). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Peripheral blood mononuclear cells | High | High expression in monocytes and macrophages |
| Small intestine | Moderate | Expression in intestinal epithelial cells (Paneth cells) |
| Colon | Moderate | Expression in intestinal epithelial cells |
| Lung | Low | Expression in alveolar macrophages |
| Spleen | Low | Expression in immune cells |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| THP-1 (monocytic leukemia) | High | Monocytic cell line, inducible by MDP |
| U937 (histiocytic lymphoma) | High | Monocytic cell line |
| HCT116 (colorectal carcinoma) | Low | Epithelial cell line, low basal expression |
| Caco-2 (colorectal adenocarcinoma) | Low | Intestinal epithelial cell line |
| HeLa (cervical carcinoma) | Low | Non-immune cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| R702W | Missense | ~8% in Crohn's disease patients (Caucasian) | Loss of function: reduced MDP-induced NF-κB activation |
| G908R | Missense | ~4% in Crohn's disease patients | Loss of function: impaired MDP recognition |
| 1007fs (Leu1007fsinsC) | Frameshift | ~8% in Crohn's disease patients | Loss of function: truncated protein, defective signaling |
| R334W | Missense | Rare, associated with Blau syndrome | Gain of function: constitutive NF-κB activation |
| R334Q | Missense | Rare, associated with Blau syndrome | Gain of function: constitutive NF-κB activation |
| L469F | Missense | Rare, associated with Blau syndrome | Gain of function: constitutive NF-κB activation |
Mutation functional classification
Loss of Function (LOF)
Mutations in the leucine-rich repeat (LRR) domain (e.g., R702W, G908R, 1007fs) impair MDP binding and downstream signaling, leading to reduced NF-κB activation and defective bacterial clearance. These are associated with Crohn's disease.
Gain of Function (GOF)
Mutations in the NACHT domain (e.g., R334W, R334Q, L469F) cause constitutive oligomerization and spontaneous NF-κB activation, leading to excessive inflammation. These are associated with Blau syndrome and early-onset sarcoidosis.
Dominant Negative (DN)
Some NOD2 variants may exert dominant-negative effects by interfering with wild-type NOD2 signaling, though this is less clearly defined. For example, certain Crohn's-associated mutations may reduce the function of the wild-type allele in heterozygous state.
View complete mutation data：
Gene Ontology (GO)
| • GO:0005515 protein binding | • GO:0005524 ATP binding |
| • GO:0004872 receptor activity | • GO:0005737 cytoplasm |
| • GO:0005829 cytosol | • GO:0007165 signal transduction |
| • GO:0007254 JNK cascade | • GO:0008063 Toll-like receptor signaling pathway |
| • GO:0009617 response to bacterium | • GO:0010008 endosome membrane |
| • GO:0032496 response to lipopolysaccharide | • GO:0032715 negative regulation of interleukin-6 production |
| • GO:0032731 positive regulation of interleukin-1 beta production | • GO:0032732 positive regulation of interleukin-1 production |
| • GO:0032735 positive regulation of interleukin-12 production | • GO:0032755 positive regulation of interleukin-6 production |
| • GO:0034162 positive regulation of toll-like receptor signaling pathway | • GO:0035666 positive regulation of NF-kappaB transcription factor activity |
| • GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling | • GO:0045087 innate immune response |
| • GO:0051092 positive regulation of NF-kappaB transcription factor activity | • GO:0051607 defense response to virus |
| • GO:0071222 cellular response to lipopolysaccharide | • GO:0071345 cellular response to cytokine stimulus |
| • GO:0071346 cellular response to interferon-gamma | • GO:0071356 cellular response to tumor necrosis factor |
| • GO:0071621 granuloma formation | • GO:1901224 positive regulation of NIK/NF-kappaB signaling |
Pathways
• NOD-like receptor signaling pathway (KEGG: hsa04621)
• Cytosolic DNA-sensing pathway (KEGG: hsa04623)
• Toll-like receptor signaling pathway (KEGG: hsa04620)
• Inflammatory bowel disease (IBD) pathway (KEGG: hsa05321)
• Apoptosis (KEGG: hsa04210)
• MAPK signaling pathway (KEGG: hsa04010)
• NF-kappa B signaling pathway (KEGG: hsa04064)
• Autophagy (KEGG: hsa04140)
• RIG-I-like receptor signaling pathway (KEGG: hsa04622)
Protein Summary
The NOD2 protein is a 1040-amino acid cytosolic receptor composed of two N-terminal caspase recruitment domains (CARDs), a central nucleotide-binding oligomerization domain (NACHT), and a C-terminal leucine-rich repeat (LRR) domain. Upon MDP binding, NOD2 undergoes ATP-dependent oligomerization and recruits RIPK2 via CARD-CARD interactions, leading to activation of NF-κB and MAPK pathways. This triggers the expression of pro-inflammatory cytokines, antimicrobial peptides, and autophagy-related genes. NOD2 also plays a role in regulating the adaptive immune response and maintaining intestinal barrier integrity. Post-translational modifications, such as phosphorylation and ubiquitination, modulate its activity.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NOD2 Knockout HEK293 Cell Line | EDJ-KQ1486 | Human | 64127 | Details Get a Quote |
| NOD2 Knockout HCT 116 Cell Line | EDJ-KQ21078 | Human | 64127 | Details Get a Quote |
| NOD2 Knockout HeLa Cell Line | EDJ-KQ57034 | Human | 64127 | Details Get a Quote |
| NOD2 Knockout A-549 Cell Line | EDJ-KQ65540 | Human | 64127 | Details Get a Quote |
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