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FLASH GENE

Symbol

NOD2

contributors: mct/ - updated : 31-03-2015

HGNC name	nucleotide-binding oligomerization domain containing 2
HGNC id	5331

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

DNA

TYPE	functioning gene
STRUCTURE	35.94 kb     12 Exon(s)

text structure

two potential integration sites

MAPPING

cloned

Y

linked

Y

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_022162 12 - 4485 NP_071445 115 1040 - 2009 19853919 also called NOD2A more abundant CaNE1 first exon variant 2 - initiation site 5500 isoform 2 112 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 variant 3 - - - isoform 3 - - - 2007 17719742 also called Alte1 alternative exon 1

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart         Digestive intestine         Homo sapiens   liver       highly Mus musculus Urinary kidney tubule       Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Epithelial absorptive excretory digestive epithelium (mucosa)   highly Homo sapiens Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic monocyte Homo sapiens Digestive epithelial cell Homo sapiens Digestive hepatocyte Mus musculus Lymphoid/Immune dendritic cell Homo sapiens Lymphoid/Immune macrophage Homo sapiens Urinary epithelial cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	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

HOMOLOGY

interspecies

ortholog to murine Card15

intraspecies

homolog to NOD1

Homologene

FAMILY	APAF1-like protein family
	cytosolic NOD-like receptor family

CATEGORY

regulatory , signaling cytokine

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
text	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

PHYSIOLOGICAL PROCESS

inflammation

text	detecting bacteria in the gut and helping control of inflammatory responses

PATHWAY

metabolism

signaling

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

INTERACTION

DNA

RNA

small molecule

protein	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

REGULATION

repressed by

TRIM27, that negatively regulates NOD2-mediated signaling by degradation of NOD2

ASSOCIATED DISORDERS

corresponding disease(s)

BLAU , IBD1 , LPRS4

Susceptibility

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

Marker

Therapy target

ANIMAL & CELL MODELS

Nod2-deficient mice were found to have increased amounts of commensals as well as reduced capability to clear newly colonizing bacteria