GENERAL INFORMATIONi
Gene namei NOD2
Synonyms BLAU, CARD15, CD, CLR16.3, IBD1, NLRC2, PSORAS1
Gene descriptioni Nucleotide binding oligomerization domain containing 2
Protein classi Disease related genes
FDA approved drug targets
Human disease related genes
Predicted locationi Intracellular
Protein evidence Evidence at protein level (all genes)
GENE INFORMATIONi
Chromosome 16
Cytoband q12.1
Chromosome location (bp) 50693588 - 50733077
Number of transcriptsi 6
Ensembl ENSG00000167207 (version 109)
Entrez gene 64127
HGNC HGNC:5331
UniProt Q9HC29 (UniProt - Evidence at protein level)
neXtProt NX_Q9HC29
GeneCards NOD2
Antibodypedia NOD2 antibodies


PROTEIN FUNCTION
Protein function (UniProt)i Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and plays an important role in gastrointestinal immunity 1, 2, 3, 4, 5, 6, 7, 8. Specifically activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan found in every bacterial peptidoglycan type 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. NOD2 specifically recognizes and binds 6-O-phospho-MDP, the phosphorylated form of MDP, which is generated by NAGK 20. 6-O-phospho-MDP-binding triggers oligomerization that facilitates the binding and subsequent activation of the proximal adapter receptor-interacting RIPK2 21, 22, 23, 24, 25. Following recruitment, RIPK2 undergoes 'Met-1'- (linear) and 'Lys-63'-linked polyubiquitination by E3 ubiquitin-protein ligases XIAP, BIRC2, BIRC3 and the LUBAC complex, becoming a scaffolding protein for downstream effectors, triggering activation of the NF-kappa-B and MAP kinases signaling 26, 27, 28, 29, 30, 31, 32, 33. This in turn leads to the transcriptional activation of hundreds of genes involved in immune response 34. Its ability to detect bacterial MDP plays a central role in maintaining the equilibrium between intestinal microbiota and host immune responses to control inflammation (By similarity). An imbalance in this relationship results in dysbiosis, whereby pathogenic bacteria prevail on commensals, causing damage in the intestinal epithelial barrier as well as allowing bacterial invasion and inflammation (By similarity). Acts as a regulator of appetite by sensing MDP in a subset of brain neurons: microbiota-derived MDP reach the brain, where they bind and activate NOD2 in inhibitory hypothalamic neurons, decreasing neuronal activity, thereby regulating satiety and body temperature (By similarity). NOD2-dependent MDP-sensing of bacterial cell walls in the intestinal epithelial compartment contributes to sustained postnatal growth upon undernutrition (By similarity). Also plays a role in antiviral response by acting as a sensor of single-stranded RNA (ssRNA) from viruses: upon ssRNA-binding, interacts with MAVS, leading to activation of interferon regulatory factor-3/IRF3 and expression of type I interferon 35. Also acts as a regulator of autophagy in dendritic cells via its interaction with ATG16L1, possibly by recruiting ATG16L1 at the site of bacterial entry 36. NOD2 activation in the small intestine crypt also contributes to intestinal stem cells survival and function: acts by promoting mitophagy via its association with ATG16L1 (By similarity). In addition to its main role in innate immunity, also regulates the adaptive immune system by acting as regulator of helper T-cell and regulatory T-cells (Tregs) (By similarity). Besides recognizing pathogens, also involved in the endoplasmic reticulum stress response: acts by sensing and binding to the cytosolic metabolite sphingosine-1-phosphate generated in response to endoplasmic reticulum stress, initiating an inflammation process that leads to activation of the NF-kappa-B and MAP kinases signaling 37, 38. May also be involved in NLRP1 activation following activation by MDP, leading to CASP1 activation and IL1B release in macrophages 39. show less
Biological process (UniProt)i Adaptive immunity, Autophagy, Immunity, Innate immunity
Ligand (UniProt)i ATP-binding, Nucleotide-binding
Gene summary (Entrez)i This gene is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing the muramyl dipeptide (MDP) derived from them and activating the NFKB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2014] show less
PROTEIN INFORMATIONi
Splice variant SwissProt TrEMBL Protein class Gene ontology Length & mass Signal peptide
(predicted)		 Transmembrane regions
(predicted)
NOD2-201
ENSP00000300589
ENST00000300589
Q9HC29
[Direct mapping] Nucleotide-binding oligomerization domain-containing protein 2
Show all
   SPOCTOPUS predicted membrane proteins
   THUMBUP predicted membrane proteins
Predicted intracellular proteins
   Intracellular proteins predicted by MDM and MDSEC
Disease related genes
FDA approved drug targets
   Small molecule drugs
Human disease related genes
   Immune system diseases
   Allergies and autoimmune diseases
   Other immune system diseases
   Skin diseases
   Skin and soft tissue diseases
Mapped to neXtProt
   neXtProt - Evidence at protein level
Show all
GO:0000166 [nucleotide binding]
GO:0002221 [pattern recognition receptor signaling pathway]
GO:0002376 [immune system process]
GO:0002606 [positive regulation of dendritic cell antigen processing and presentation]
GO:0002720 [positive regulation of cytokine production involved in immune response]
GO:0002830 [positive regulation of type 2 immune response]
GO:0003779 [actin binding]
GO:0005515 [protein binding]
GO:0005524 [ATP binding]
GO:0005737 [cytoplasm]
GO:0005739 [mitochondrion]
GO:0005794 [Golgi apparatus]
GO:0005829 [cytosol]
GO:0005856 [cytoskeleton]
GO:0005886 [plasma membrane]
GO:0006952 [defense response]
GO:0009595 [detection of biotic stimulus]
GO:0009986 [cell surface]
GO:0016020 [membrane]
GO:0016045 [detection of bacterium]
GO:0016323 [basolateral plasma membrane]
GO:0019899 [enzyme binding]
GO:0019901 [protein kinase binding]
GO:0030277 [maintenance of gastrointestinal epithelium]
GO:0030544 [Hsp70 protein binding]
GO:0031347 [regulation of defense response]
GO:0031982 [vesicle]
GO:0032495 [response to muramyl dipeptide]
GO:0032498 [detection of muramyl dipeptide]
GO:0032500 [muramyl dipeptide binding]
GO:0032731 [positive regulation of interleukin-1 beta production]
GO:0032733 [positive regulation of interleukin-10 production]
GO:0032740 [positive regulation of interleukin-17 production]
GO:0032755 [positive regulation of interleukin-6 production]
GO:0032757 [positive regulation of interleukin-8 production]
GO:0032760 [positive regulation of tumor necrosis factor production]
GO:0032874 [positive regulation of stress-activated MAPK cascade]
GO:0032991 [protein-containing complex]
GO:0035556 [intracellular signal transduction]
GO:0038187 [pattern recognition receptor activity]
GO:0042742 [defense response to bacterium]
GO:0042834 [peptidoglycan binding]
GO:0042981 [regulation of apoptotic process]
GO:0043123 [positive regulation of I-kappaB kinase/NF-kappaB signaling]
GO:0043406 [positive regulation of MAP kinase activity]
GO:0043552 [positive regulation of phosphatidylinositol 3-kinase activity]
GO:0044877 [protein-containing complex binding]
GO:0045087 [innate immune response]
GO:0045335 [phagocytic vesicle]
GO:0045747 [positive regulation of Notch signaling pathway]
GO:0045944 [positive regulation of transcription by RNA polymerase II]
GO:0046330 [positive regulation of JNK cascade]
GO:0046645 [positive regulation of gamma-delta T cell activation]
GO:0050679 [positive regulation of epithelial cell proliferation]
GO:0050700 [CARD domain binding]
GO:0050727 [regulation of inflammatory response]
GO:0050871 [positive regulation of B cell activation]
GO:0051092 [positive regulation of NF-kappaB transcription factor activity]
GO:0051353 [positive regulation of oxidoreductase activity]
GO:0051770 [positive regulation of nitric-oxide synthase biosynthetic process]
GO:0051879 [Hsp90 protein binding]
GO:0060585 [positive regulation of prostaglandin-endoperoxide synthase activity]
GO:0070374 [positive regulation of ERK1 and ERK2 cascade]
GO:0070431 [nucleotide-binding oligomerization domain containing 2 signaling pathway]
GO:0071222 [cellular response to lipopolysaccharide]
GO:0071225 [cellular response to muramyl dipeptide]
GO:1900017 [positive regulation of cytokine production involved in inflammatory response]
GO:1901224 [positive regulation of NIK/NF-kappaB signaling]
GO:1902523 [positive regulation of protein K63-linked ubiquitination]
GO:2000110 [negative regulation of macrophage apoptotic process]
GO:2000363 [positive regulation of prostaglandin-E synthase activity]
Show all
 1040 aa
115.3 kDa 		No 0
NOD2-205
ENSP00000435149
ENST00000527070
E9PLF7
[Direct mapping] Nucleotide-binding oligomerization domain-containing protein 2
Show all
Predicted intracellular proteins
   Intracellular proteins predicted by MDM and MDSEC
Human disease related genes
   Immune system diseases
   Allergies and autoimmune diseases
   Other immune system diseases
   Skin diseases
   Skin and soft tissue diseases
Show all
GO:0042981 [regulation of apoptotic process]
Show all
 266 aa
29.8 kDa 		No 0
NOD2-207
ENSP00000431681
ENST00000531674
E9PK30
[Direct mapping] Nucleotide-binding oligomerization domain-containing protein 2
Show all
Predicted intracellular proteins
   Intracellular proteins predicted by MDM and MDSEC
Human disease related genes
   Immune system diseases
   Allergies and autoimmune diseases
   Other immune system diseases
   Skin diseases
   Skin and soft tissue diseases
Show all
GO:0042981 [regulation of apoptotic process]
Show all
 146 aa
16.8 kDa 		No 0
NOD2-209
ENSP00000437246
ENST00000534057
H0YF53
[Direct mapping] Nucleotide-binding oligomerization domain-containing protein 2
Show all
Predicted intracellular proteins
   Intracellular proteins predicted by MDM and MDSEC
Human disease related genes
   Immune system diseases
   Allergies and autoimmune diseases
   Other immune system diseases
   Skin diseases
   Skin and soft tissue diseases
Show all
GO:0005515 [protein binding]
Show all
 169 aa
17.9 kDa 		No 0
NOD2-213
ENSP00000495993
ENST00000647318
Q9HC29
[Direct mapping] Nucleotide-binding oligomerization domain-containing protein 2
Show all
   SPOCTOPUS predicted membrane proteins
   THUMBUP predicted membrane proteins
Predicted intracellular proteins
   Intracellular proteins predicted by MDM and MDSEC
Disease related genes
FDA approved drug targets
   Small molecule drugs
Human disease related genes
   Immune system diseases
   Allergies and autoimmune diseases
   Other immune system diseases
   Skin diseases
   Skin and soft tissue diseases
Mapped to neXtProt
   neXtProt - Evidence at protein level
Show all
GO:0000165 [MAPK cascade]
GO:0000166 [nucleotide binding]
GO:0002221 [pattern recognition receptor signaling pathway]
GO:0002227 [innate immune response in mucosa]
GO:0002253 [activation of immune response]
GO:0002376 [immune system process]
GO:0002606 [positive regulation of dendritic cell antigen processing and presentation]
GO:0002710 [negative regulation of T cell mediated immunity]
GO:0002720 [positive regulation of cytokine production involved in immune response]
GO:0002732 [positive regulation of dendritic cell cytokine production]
GO:0002815 [biosynthetic process of antibacterial peptides active against Gram-positive bacteria]
GO:0002830 [positive regulation of type 2 immune response]
GO:0002862 [negative regulation of inflammatory response to antigenic stimulus]
GO:0002925 [positive regulation of humoral immune response mediated by circulating immunoglobulin]
GO:0003779 [actin binding]
GO:0005515 [protein binding]
GO:0005524 [ATP binding]
GO:0005737 [cytoplasm]
GO:0005739 [mitochondrion]
GO:0005794 [Golgi apparatus]
GO:0005829 [cytosol]
GO:0005856 [cytoskeleton]
GO:0005886 [plasma membrane]
GO:0006909 [phagocytosis]
GO:0006952 [defense response]
GO:0006963 [positive regulation of antibacterial peptide biosynthetic process]
GO:0006965 [positive regulation of biosynthetic process of antibacterial peptides active against Gram-positive bacteria]
GO:0007249 [I-kappaB kinase/NF-kappaB signaling]
GO:0007254 [JNK cascade]
GO:0007584 [response to nutrient]
GO:0008284 [positive regulation of cell population proliferation]
GO:0009595 [detection of biotic stimulus]
GO:0009986 [cell surface]
GO:0010936 [negative regulation of macrophage cytokine production]
GO:0016020 [membrane]
GO:0016045 [detection of bacterium]
GO:0016323 [basolateral plasma membrane]
GO:0018108 [peptidyl-tyrosine phosphorylation]
GO:0019899 [enzyme binding]
GO:0019901 [protein kinase binding]
GO:0030277 [maintenance of gastrointestinal epithelium]
GO:0030544 [Hsp70 protein binding]
GO:0031347 [regulation of defense response]
GO:0031398 [positive regulation of protein ubiquitination]
GO:0031982 [vesicle]
GO:0032088 [negative regulation of NF-kappaB transcription factor activity]
GO:0032494 [response to peptidoglycan]
GO:0032495 [response to muramyl dipeptide]
GO:0032496 [response to lipopolysaccharide]
GO:0032498 [detection of muramyl dipeptide]
GO:0032500 [muramyl dipeptide binding]
GO:0032689 [negative regulation of interferon-gamma production]
GO:0032695 [negative regulation of interleukin-12 production]
GO:0032701 [negative regulation of interleukin-18 production]
GO:0032703 [negative regulation of interleukin-2 production]
GO:0032720 [negative regulation of tumor necrosis factor production]
GO:0032731 [positive regulation of interleukin-1 beta production]
GO:0032733 [positive regulation of interleukin-10 production]
GO:0032735 [positive regulation of interleukin-12 production]
GO:0032740 [positive regulation of interleukin-17 production]
GO:0032755 [positive regulation of interleukin-6 production]
GO:0032757 [positive regulation of interleukin-8 production]
GO:0032760 [positive regulation of tumor necrosis factor production]
GO:0032874 [positive regulation of stress-activated MAPK cascade]
GO:0032991 [protein-containing complex]
GO:0034134 [toll-like receptor 2 signaling pathway]
GO:0034136 [negative regulation of toll-like receptor 2 signaling pathway]
GO:0035556 [intracellular signal transduction]
GO:0038061 [NIK/NF-kappaB signaling]
GO:0038187 [pattern recognition receptor activity]
GO:0042742 [defense response to bacterium]
GO:0042834 [peptidoglycan binding]
GO:0042981 [regulation of apoptotic process]
GO:0043123 [positive regulation of I-kappaB kinase/NF-kappaB signaling]
GO:0043330 [response to exogenous dsRNA]
GO:0043406 [positive regulation of MAP kinase activity]
GO:0043410 [positive regulation of MAPK cascade]
GO:0043552 [positive regulation of phosphatidylinositol 3-kinase activity]
GO:0044877 [protein-containing complex binding]
GO:0045087 [innate immune response]
GO:0045089 [positive regulation of innate immune response]
GO:0045335 [phagocytic vesicle]
GO:0045747 [positive regulation of Notch signaling pathway]
GO:0045944 [positive regulation of transcription by RNA polymerase II]
GO:0046330 [positive regulation of JNK cascade]
GO:0046645 [positive regulation of gamma-delta T cell activation]
GO:0050679 [positive regulation of epithelial cell proliferation]
GO:0050700 [CARD domain binding]
GO:0050727 [regulation of inflammatory response]
GO:0050731 [positive regulation of peptidyl-tyrosine phosphorylation]
GO:0050766 [positive regulation of phagocytosis]
GO:0050830 [defense response to Gram-positive bacterium]
GO:0050871 [positive regulation of B cell activation]
GO:0051092 [positive regulation of NF-kappaB transcription factor activity]
GO:0051353 [positive regulation of oxidoreductase activity]
GO:0051403 [stress-activated MAPK cascade]
GO:0051649 [establishment of localization in cell]
GO:0051770 [positive regulation of nitric-oxide synthase biosynthetic process]
GO:0051879 [Hsp90 protein binding]
GO:0060585 [positive regulation of prostaglandin-endoperoxide synthase activity]
GO:0060907 [positive regulation of macrophage cytokine production]
GO:0070371 [ERK1 and ERK2 cascade]
GO:0070374 [positive regulation of ERK1 and ERK2 cascade]
GO:0070431 [nucleotide-binding oligomerization domain containing 2 signaling pathway]
GO:0071222 [cellular response to lipopolysaccharide]
GO:0071224 [cellular response to peptidoglycan]
GO:0071225 [cellular response to muramyl dipeptide]
GO:0071407 [cellular response to organic cyclic compound]
GO:0071639 [positive regulation of monocyte chemotactic protein-1 production]
GO:0090022 [regulation of neutrophil chemotaxis]
GO:0098792 [xenophagy]
GO:1900017 [positive regulation of cytokine production involved in inflammatory response]
GO:1901224 [positive regulation of NIK/NF-kappaB signaling]
GO:1902523 [positive regulation of protein K63-linked ubiquitination]
GO:1904417 [positive regulation of xenophagy]
GO:2000110 [negative regulation of macrophage apoptotic process]
GO:2000363 [positive regulation of prostaglandin-E synthase activity]
Show all
 1013 aa
112.5 kDa 		No 0
NOD2-215
ENSP00000513311
ENST00000697426
Predicted intracellular proteins
   Intracellular proteins predicted by MDM and MDSEC
Human disease related genes
   Immune system diseases
   Allergies and autoimmune diseases
   Other immune system diseases
   Skin diseases
   Skin and soft tissue diseases
Show all
GO:0005515 [protein binding]
Show all
 169 aa
18.2 kDa 		No 0

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