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Symbol NOD2 contributors: mct/ - updated : 31-03-2015
HGNC name nucleotide-binding oligomerization domain containing 2
HGNC id 5331
Corresponding disease
BLAU Blau syndrome
IBD1 chronic inflammatory bowel disease, 1
LPRS4 leprosy, susceptibility locus 4
Location 16q12.1      Physical location : 50.731.049 - 50.766.987
Synonym name
  • caspase recruitment domain family, member 15
  • LRR containing protein
  • NLR family, CARD domain containing 2
  • NOD-like receptor C2
  • NOD-like receptor C2
  • nucleotide-binding oligomerization domain, leucine rich repeat and CARD domain containing 2
  • inflammatory bowel disease protein 1
  • Synonym symbol(s) CDIBD1, ACUG, CARF, CARD15, CLR16.3, NLRC2, NOD2B, CD, PSORAS1
    TYPE functioning gene
    STRUCTURE 35.94 kb     12 Exon(s)
    text structure two potential integration sites
    MAPPING cloned Y linked Y status confirmed
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    12 - 4485 115 1040 - 2009 19853919
  • also called NOD2A
  • more abundant
  • CaNE1 first exon
  • - initiation site 5500 112 1013 in blood monocytes 2007 17719742
  • also called NOD2B
  • is 27 amino acids shorter than previously reported, starting at a conserved methionine in exon 2
  • - - - - - - 2007 17719742
  • also called Alte1
  • alternative exon 1
    Type restricted
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestine     Homo sapiens
     liver   highly Mus musculus
    Urinarykidneytubule    Homo sapiens
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Epithelialabsorptive excretorydigestive epithelium (mucosa) highly Homo sapiens
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticmonocyte Homo sapiens
    Digestiveepithelial cell Homo sapiens
    Digestivehepatocyte Mus musculus
    Lymphoid/Immunedendritic cell Homo sapiens
    Lymphoid/Immunemacrophage Homo sapiens
    Urinaryepithelial cell Homo sapiens
    cell lineage
    cell lines
    at STAGE
  • two N-terminal CARD (caspase recruitment) domains
  • a P loop (Walker A)
  • a Mg2+ binding site
  • a central nucleotide binding domain (NBD), NAD and NACHT domain
  • ten tandem leucine-rich repeats at the C terminus
    interspecies ortholog to murine Card15
    intraspecies homolog to NOD1
  • APAF1-like protein family
  • cytosolic NOD-like receptor family
  • CATEGORY regulatory , signaling cytokine
    SUBCELLULAR LOCALIZATION     intracellular
  • restricted to the cytosol
  • basic FUNCTION
  • acting as a regulator of inflammatory responses
  • playing 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
  • NOD2 activation induce chitinase expression in macrophages
  • potentially responsible for the membrane recruitment of RIPK2 to induce a regulated NF-kappaB signaling and production of proinflammatory cytokines
  • can function as a cytoplasmic viral pattern-recognition receptors by triggering activation of interferon-regulatory factor 3 (IRF3) and production of interferon-beta (IFN-beta)
  • important role of its signaling in crypt function
  • required to induce bactericidal activity in crypt secretions of the terminal ileum (essential for the control of both Gram-positive and Gram-negative commensal microbiota in the terminal ileum)
  • may have a a regulatory role whereby NOD2 enhances the function of RNASEL
  • NOD1 and NOD2 play an important role in the pathogenesis of acute ischemic injury of the kidney, although possibly through different mechanisms
  • NOD2 and TRIM27 might functionally cooperate in the nucleus
  • plays an important role in intestinal immune homeostasis
  • NOD1 and NOD2 are intracellular pattern recognition receptors that activate inflammation and autophagy
  • CELLULAR PROCESS cell life, cell death/apoptosis
  • detecting bacteria in the gut and helping control of inflammatory responses
    critical role for the NOD2-RIPK2 pathway in regulating homeostasis between bacterial flora and innate immunity
    a component
  • ATG16L1 and NOD2 are components of an autophagy-mediated antibacterial pathway that is altered in a cell- and function-specific manner by Crohn disease-associated mutations
    small molecule
  • activating NFKB
  • interacting with RIPK2 (RICK) via an homophilic CARD interaction
  • RIPK2 determines its stability and consequently NOD1- and NOD2-mediated immune responses
  • role for XIAP in regulating innate immune responses by interacting with NOD1 and NOD2 through interaction with RIPK2
  • OAS2 binding partner for NOD2
  • binds to the scaffolding protein kinase, RIP2 (receptor-interacting protein 2), via caspase recruitment domain interactions
  • CARD8 physically interacts with NOD2 and inhibits nodosome assembly and subsequent signaling upon muramyl-dipeptide stimulation
  • TRAF4, is a key negative regulator of NOD2 signaling
  • binding of TRAF4 to NOD2, is required for TRAF4 phosphorylation and subsequent inhibition of NOD2 signaling
  • XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2
  • NOD2 stimulates autophagy in a process dependent on RIPK2 tyrosine kinase activity
  • MAPKBP1 through its WD-40 domain, binds to NOD2 (this interaction attenuates NOD2-mediated NFKB1 activation and IL8 secretion as well as NOD2 antibacterial activity)
  • TRIM27 is a new specific binding partner for NOD2
  • a ubiquitin-regulated signaling network centered on ITCH and BIRC2 controls the strength of NOD2 signaling
  • FRMPD2 interacts with NOD2 via leucine-rich repeats and forms a complex with the membrane-associated protein ERBIN
  • ANKRD17 is a novel binding partner of NOD2 and its N-terminal domain mediates NOD2 binding
  • function of NOD2 for the regulation of TRPC6 channels, suggesting that TRPC6-dependent Ca(2+) signaling is one of the critical signal transduction pathways that links innate immunity mediator NOD2 to podocyte injury
  • RIPK2 is a substrate for PELI3 and PELI3 is an important mediator in the NOD2 pathway and regulator of intestinal inflammation
  • NFKB1 inhibits NOD2-induced cytokine secretion through ATF3-dependent mechanisms
  • TWIST1 and TWIST2 were required for optimal cytokine downregulation during acute and, particularly, chronic NOD2 stimulation of human macrophages
  • cell & other
  • with intestinal commensal bacterial flora maintain a balance by regulating each other through a feedback mechanism
    repressed by TRIM27, that negatively regulates NOD2-mediated signaling by degradation of NOD2
    corresponding disease(s) BLAU , IBD1 , LPRS4
  • to leprosy
  • to Crohn disease (in North-Europeans people)
  • to psoriatic arthritis
  • to ulcerative colitis in Italian people
  • R702W, G908R, 3020insC strongly associated with crohn disease (ileal form) but not with ulcerative colitis
  • to early-onset sarcoidosis (minor role)
  • to SAPHO syndrome
  • Variant & Polymorphism SNP , other
  • SNP13 increased risk for right colonic or fibrostenotic Crohn disease of the small bowel
  • SNP8-SNP12 increased risk for ileal Crohn disease
  • 3020insC increases susceptibility to Crohn's disease
  • mutated in early-onset sarcoidosis
  • variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae
  • association between CNV in NOD2, and SAPHO syndrome
  • Candidate gene
    Therapy target
    Nod2-deficient mice were found to have increased amounts of commensals as well as reduced capability to clear newly colonizing bacteria