Nucleotide-binding oligomerization domain-containing protein 2

UniProt Q9HC29 Organism Homo sapiens Gene CARD15, NOD2

Also known as: CARD15, NOD2

Function

Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and plays an important role in gastrointestinal immunity. Specifically activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan found in every bacterial peptidoglycan type. NOD2 specifically recognizes and binds 6-O-phospho-MDP, the phosphorylated form of MDP, which is generated by NAGK. 6-O-phospho-MDP-binding triggers oligomerization that facilitates the binding and subsequent activation of the proximal adapter receptor-interacting RIPK2. 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. This in turn leads to the transcriptional activation of hundreds of genes involved in immune response. 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. 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. 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. May also be involved in NLRP1 activation following activation by MDP, leading to CASP1 activation and IL1B release in macrophages.

Classification

Family (Pfam): PF00619 CARD, PF13516 LRR_6, PF05729 NACHT, PF17776 NLRC4_HD2, PF17779 WHD_NOD2
InterPro: CARD, DEATH-like_dom_sf, Leu-rich_rpt, LRR_dom_sf, NACHT_NTPase, NLR, NLRP_HD2, NOD1/2_WH, P-loop_NTPase
Functional cluster: Secreted Growth Factors & Cytokines

Gene Ontology · 73

Disease associations

Blau syndrome MONDO:0008523
inflammatory bowel disease 1 MONDO:0009960
Yao syndrome MONDO:0015019

Drugs targeting this protein · 1

MIFAMURTIDE other

Neighborhood · nearest proteins

Nearest neighbours of Nucleotide-binding oligomerization domain-containing protein 2: 3 by sequence/function similarity (left); 3 co-cited in the literature (right).

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Nucleotide-binding oligomerization domain-containing protein 1 8 shared papers
Nucleotide-binding oligomerization domain-containing protein 2 1 shared papers
Receptor-interacting serine/threonine-protein kinase 2 10 shared papers
Nucleotide-binding oligomerization domain-containing protein 2 5 shared papers
Palmitoyltransferase ZDHHC5 2 shared papers
Mitogen-activated protein kinase-binding protein 1 1 shared papers
Autophagy-related protein 16-1 3 shared papers
Zinc finger protein RFP 1 shared papers
NACHT, LRR and PYD domains-containing protein 12 1 shared papers
Immunity-related GTPase family M protein 2 shared papers
N-acetyl-D-glucosamine kinase 1 shared papers
Erbin 1 shared papers

Literature · 62 cited papers

Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection. EMBO J. · 2022
Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation. Nature · 2022
Palmitoylation restricts SQSTM1/p62-mediated autophagic degradation of NOD2 to modulate inflammation. Cell Death Differ. · 2022
S-palmitoylation of NOD2 controls its localization to the plasma membrane. J. Lipid Res. · 2021
A novel pathogenic NOD2 variant in a mother and daughter with Blau syndrome. Ophthalmic Genet. · 2021
Cellular stress promotes NOD1/2-dependent inflammation via the endogenous metabolite sphingosine-1-phosphate. EMBO J. · 2021
Palmitoylation of NOD1 and NOD2 is required for bacterial sensing. Science · 2019
Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens. Nat. Commun. · 2018
Structural basis of RIP2 activation and signaling. Nat. Commun. · 2018
RIP2 filament formation is required for NOD2 dependent NF-kappaB signalling. Nat. Commun. · 2018
An inflammatory bowel disease-risk variant in INAVA decreases pattern recognition receptor-induced outcomes. J. Clin. Invest. · 2017
Characterization and Genetic Analyses of New Genes Coding for NOD2 Interacting Proteins. PLoS ONE · 2016
… and 50 more in the literature graph

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