Q8K3Z0
uniprot
Q8K3Z0
canonical
activity_regulation
ACTIVITY REGULATION: ADP-binding promotes an inactive closed conformation. {ECO:0000250|UniProtKB:G1T469}.
uniprot
proteins
amino_acid_sequence
MRSSCCDMCSQEEFQAQRSQLVALLISGSLEGFESILDWLLSWDVLSREDYEGLSLPGQPLSHSARRLLDTVWNKGVWGCQKLLEAVQEAQANSHTFELYGSWDTHSLHPTRDLQSHRPAIVRRLYNHVEAMLELAREGGFLSQYECEEIRLPIFTSSQRARRLLDLAAVKANGLAAFLLQHVRELPAPLPLPYEAAECQKFISKLRTMVLTQSRFLSTYDGSENLCLEDIYTENILELQTEVGTAGALQKSPAILGLEDLFDTHGHLNRDADTILVVGEAGSGKSTLLQRLHLLWATGRSFQEFLFIFPFSCRQLQCVAKPLSLRTLLFEHCCWPDVAQDDVFQFLLDHPDRVLLTFDGLDEFKFRFTDRERHCSPIDPTSVQTLLFNLLQGNLLKNACKVLTSRPDAVSALLRKFVRTELQLKGFSEEGIQLYLRKHHREPGVADRLIQLIQATSALHGLCHLPVFSWMVSRCHRELLLQNRGFPTTSTDMYLLILQHFLLHASPPDSSPLGLGPGLLQSRLSTLLHLGHLALRGLAMSCYVFSAQQLQAAQVDSDDISLGFLVRAQSSVPGSKAPLEFLHITFQCFFAAFYLAVSADTSVASLKHLFSCGRLGSSLLGRLLPNLCIQGSRVKKGSEAALLQKAEPHNLQITAAFLAGLLSQQHRDLLAACQVSERVLLQRQARARSCLAHSLREHFHSIPPAVPGETKSMHAMPGFIWLIRSLYEMQEEQLAQEAVRRLDIGHLKLTFCRVGPAECAALAFVLQHLQRPVALQLDYNSVGDVGVEQLRPCLGVCTALYLRDNNISDRGARTLVECALRCEQLQKLALFNNKLTDACACSMAKLLAHKQNFLSLRVGNNHITAAGAEVLAQGLKSNTSLKFLGFWGNSVGDKGTQALAEVVADHQNLKWLSLVGNNIGSMGAEALALMLEKNKSLEELCLEENHICDEGVYSLAEGLKRNSTLKFLKLSNNGITYRGAEALLQALSRNSAILEVWLRGNTFSLEEIQTLSSRDARLLL
uniprot
proteins
function
FUNCTION: Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and plays an important role in gastrointestinal immunity (PubMed:15692051, PubMed:15692052, PubMed:19805227, PubMed:21715553). Specifically activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan found in every bacterial peptidoglycan type (PubMed:15692051, PubMed:15692052, PubMed:25429073). NOD2 specifically recognizes and binds 6-O-phospho-MDP, the phosphorylated form of MDP, which is generated by NAGK (PubMed:36002575). 6-O-phospho-MDP-binding triggers oligomerization that facilitates the binding and subsequent activation of the proximal adapter receptor-interacting RIPK2 (PubMed:15692051, PubMed:15692052, PubMed:22607974). 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 (PubMed:15692051, PubMed:15692052, PubMed:22607974). This in turn leads to the transcriptional activation of hundreds of genes involved in immune response (PubMed:22607974). Its ability to detect bacterial MDP plays a central role in maintaining the equilibrium between intestinal microbiota and host immune responses to control inflammation (PubMed:19805227, PubMed:21421666, PubMed:23281400, PubMed:24062413, PubMed:24882705, PubMed:25088769, PubMed:25666722, PubMed:28127403). 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 (PubMed:23281400, PubMed:25088769). 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 (PubMed:35420957). NOD2-dependent MDP-sensing of bacterial cell walls in the intestinal epithelial compartment contributes to sustained postnatal growth upon undernutrition (PubMed:36821686). 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 (By similarity). 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 (PubMed:19898471, PubMed:19966812, PubMed:27230380). 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 (PubMed:31919280). 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) (PubMed:21856952, PubMed:27230380). 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 (PubMed:27007849). May also be involved in NLRP1 activation following activation by MDP, leading to CASP1 activation and IL1B release in macrophages (PubMed:18511561). {ECO:0000250|UniProtKB:G1T469, ECO:0000269|PubMed:15692051, ECO:0000269|PubMed:15692052, ECO:0000269|PubMed:18511561, ECO:0000269|PubMed:19805227, ECO:0000269|PubMed:19898471, ECO:0000269|PubMed:19966812, ECO:0000269|PubMed:21421666, ECO:0000269|PubMed:21715553, ECO:0000269|PubMed:21856952, ECO:0000269|PubMed:22607974, ECO:0000269|PubMed:23281400, ECO:0000269|PubMed:24062413, ECO:0000269|PubMed:24882705, ECO:0000269|PubMed:25088769, ECO:0000269|PubMed:25429073, ECO:0000269|PubMed:25666722, ECO:0000269|PubMed:27007849, ECO:0000269|PubMed:27230380, ECO:0000269|PubMed:28127403, ECO:0000269|PubMed:31919280, ECO:0000269|PubMed:35420957, ECO:0000269|PubMed:36002575, ECO:0000269|PubMed:36821686}.
uniprot
proteins
mass_dalton
113562
uniprot
proteins
mutagenesis
MUTAGEN 314; /note="R->Q: Mutation that mimics a human variant associated with Blau syndrome (BLAUS); knockin mice show impaired response to muramyl dipeptide."; /evidence="ECO:0000269|PubMed:25429073"; MUTAGEN 987..1020; /note="LSRNSAILEVWLRGNTFSLEEIQTLSSRDARLLL->P: Mutation that mimics human L1007fsinsC variant; knockin mice show elevated NF-kappa-B activation in response to muramyl dipeptide and more efficient processing and secretion of the cytokine IL1B."; /evidence="ECO:0000269|PubMed:15692052
uniprot
proteins
post_translational_modification
PTM: Palmitoylated by ZDHHC5; palmitoylation is required for proper recruitment to the bacterial entry site and hence for proper signaling upon cognate peptidoglycan detection (By similarity). Palmitoylation promotes localization to the cell membrane (By similarity). Palmitoylation protects from SQSTM1/p62-dependent autophagic degradation (By similarity). {ECO:0000250|UniProtKB:Q9HC29, ECO:0000250|UniProtKB:Q9Y239}.; PTM: Polyubiquitinated by TRIM27, leading to proteasome-mediated degradation (By similarity). Polyubiquitinated and degraded following muramyl dipeptide (MDP) stimulation, conferring MDP tolerance and preventing septic shock (By similarity). {ECO:0000250|UniProtKB:Q9HC29}.; PTM: Degraded via selective autophagy following interaction with Irgm1. Irgm1 promotes NOD2-RIPK2 RIPosome recruitment to autophagosome membranes, promoting their SQSTM1/p62-dependent autophagic degradation. {ECO:0000250|UniProtKB:Q9HC29}.; PTM: O-glycosylated by OGT, O-GlcNAcylation increases protein stability. {ECO:0000250|UniProtKB:Q9HC29}.
uniprot
proteins
protein_family
NOD1-NOD2 family
uniprot
proteins
pubmed
12835899
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15692051
uniprot
proteins
pubmed
15692052
uniprot
proteins
pubmed
16203728
uniprot
proteins
pubmed
17187069
uniprot
proteins
pubmed
18511561
uniprot
proteins
pubmed
19805227
uniprot
proteins
pubmed
19898471
uniprot
proteins
pubmed
19966812
uniprot
proteins
pubmed
21421666
uniprot
proteins
pubmed
21715553
uniprot
proteins
pubmed
21856952
uniprot
proteins
pubmed
22607974
uniprot
proteins
pubmed
23019338
uniprot
proteins
pubmed
23281400
uniprot
proteins
pubmed
24062413
uniprot
proteins
pubmed
24882705
uniprot
proteins
pubmed
25088769
uniprot
proteins
pubmed
25429073
uniprot
proteins
pubmed
25666722
uniprot
proteins
pubmed
27007849
uniprot
proteins
pubmed
27230380
uniprot
proteins
pubmed
28127403
uniprot
proteins
pubmed
31919280
uniprot
proteins
pubmed
35420957
uniprot
proteins
pubmed
36002575
uniprot
proteins
pubmed
36821686
uniprot
proteins
sequence_length
1020
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q9HC29}; Lipid-anchor {ECO:0000250|UniProtKB:Q9HC29}. Basolateral cell membrane {ECO:0000250|UniProtKB:Q9HC29}. Cytoplasm {ECO:0000250|UniProtKB:Q9HC29}. Mitochondrion {ECO:0000250|UniProtKB:Q9HC29}. Note=Palmitoylation promotes localization to the cell membrane, where it detects bacterial invasion at the point of entry. {ECO:0000250|UniProtKB:Q9HC29}.
uniprot
proteins