InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Gene: NOD2

Summary

InnateDB Gene

IDBG-30654.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

NOD2

Gene Name

nucleotide-binding oligomerization domain containing 2

Synonyms

Species

Homo sapiens

Ensembl Gene

ENSG00000167207

Encoded Proteins

IDBP-30656

nucleotide-binding oligomerization domain containing 2

IDBP-602551

nucleotide-binding oligomerization domain containing 2

IDBP-602755

nucleotide-binding oligomerization domain containing 2

IDBP-752726

IDBP-750841

IDBP-749098

IDBP-749009

IDBP-584481

nucleotide-binding oligomerization domain containing 2

Protein Structure

Useful resources

Stemformatics EHFPI ImmGen

InnateDB Annotation

Summary

PMID 17690884

NOD2 and NOD1 represent central players in the control of the immune responses to bacterial infections and inflammation.

PMID 18240302

NOD2 is an intracellular receptor of muramyl dipeptide (MDP), a component of peptidoglycan present in the cell wall of Gram-positive (G+) and Gram-negative (G-) bacteria.

PMID 17705131

NOD2 and NOD1 can induce CCL5 (RANTES) through NF-kappaB pathway, orchestrating the global Nod-dependent immune defence during bacterial infections.

PMID 19541630

NOD2-dependent recognition of S. aureus and muramyl dipeptide is facilitated by alpha-toxin (alpha-hemolysin), a pore-forming toxin and virulence factor of the pathogen and is dependent on IL-1beta-amplified production of IL-6.

PMID 19898471

NOD2 and NOD1 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry.

PMID 19966812

NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation.

PMID 20200479

NOD2 recruits the critical autophagy protein ATG16L1 to the plasma membrane during bacterial invasion.

PMID 19701189

NOD2 functions as a cytoplasmic viral pattern-recognition receptor (PRR) and activates an innate immune responses to viral ssRNA by triggering activation of interferon-regulatory factor 3 (IRF3) and production of interferon-beta (IFNB1).

PMID 21199260

NOD2 is both a positive and negative regulator of TLR4 - the effect it exerts is dependent on the presence of MDP. NOD2 upon engagement with its ligand, MDP, positively regulates TLR4-mediated signalling; in the absence of MDP, NOD2 negatively regulates the TLR4 pathway. (Demonstrated in murine model)

PMID 21236705

NOD2 is a peripheral peptidoglycan intracellular sensor and is important for the progression and pathogenesis of experimental autoimmune encephalomyelitis (animal model of multiple sclerosis).

PMID 21108472

NOD2 detects heat-killed Legionella pneumophila and stimulates NFkB and IFN-beta promoter activity. NOD2 deficiency results in increased proinflammatory cytokine expression at 4hrs and greater neutrophil recruitment to the lung. (Demonstrated in murine model)

PMID 21690088

DDX58 and NOD2 colocalize to cellular ruffles and cell-cell junctions to form a protein complex via the CARD domains. DDX58 negatively regulates ligand-induced NFkB signalling mediated by NOD2, and conversely, NOD2 negatively regulates type I interferon induction by DDX58.

PMID 22750073

NOD2 recognition of muramyl dipeptide, a component of bacterial cell walls, improves the barrier function of intestinal epithelial cells. (Demonstrated in mice)

PMID 22531915

NOD2 enhances the innate immune response of alveolar macrophages to Mycobacterium tuberculosis in human.

PMID 24670424

Following NOD2 activation, IRF4 interacts with MYD88, TRAF6, and RIPK2 and downregulates K63-linked polyubiquitinylation of RICK and TRAF6 leading to disruption of NFkB activation pathways.

PMID 25433720

NOD2 plays a role in intestinal innate immunity by regulating the expression of DEFA5 and DEFA6 through the NF-kB and MAPK pathways.

InnateDB Annotation from Orthologs

Summary

PMID 18981137

[Mus musculus] Nod2-deficient mice have impaired resistance to Mycobacterium tuberculosis infection through defective innate and adaptive immunity.

PMID 20679225

[Mus musculus] Nod2 functions in non-hematopoietic cells of the small intestinal crypts and this is critical for protecting mice from a Th1-driven granulomatous inflammation in the ilum.

PMID 20685341

[Mus musculus] Nod2 and Nod1 account for neutrophil recruitment to the lungs of mice infected with Legionella pneumophila.

PMID 17705131

[Mus musculus] Nod2 and Nod1 activation results in substantial secretion of Ccl5 by murine macrophages and induces binding of NF-kappaB subunits to Ccl5 promoter.

PMID 21072876

[Mus musculus] Nod2 and Nod1 can detect Legionella pneumophila and these receptors modulate the in vivo pulmonary immune response differently.

PMID 21199260

[Mus musculus] Nod2 is both a positive and negative regulator of Tlr4 - the effect it exerts is dependent on the presence of MDP. Nod2 upon engagement with its ligand, MDP, positively regulates Tlr4-mediated signaling; in the absence of MDP, Nod2 negatively regulates the Tlr4 pathway.

PMID 21236705

[Mus musculus] Nod2 is a peripheral peptidoglycan intracellular sensor and is important for the progression and pathogenesis of experimental autoimmune encephalomyelitis (animal model of multiple sclerosis).

PMID 21108472

[Mus musculus] Nod2 detects heat-killed Legionella pneumophila and stimulates NFkB and IFN-beta promoter activity. Nod2 deficiency results in increased proinflammatory cytokine expression at 4hrs and greater neutrophil recruitment to the lung.

PMID 21690088

[Mus musculus] Ddx58 and Nod2 colocalize to cellular ruffles and cell-cell junctions to form a protein complex via the CARD domains. Ddx58 negatively regulates ligand-induced NFkB signalling mediated by Nod2, and conversely, Nod2 negatively regulates type I interferon induction by Ddx58. (Demonstrated in human)

PMID 22750073

[Mus musculus] Nod2 recognition of muramyl dipeptide, a component of bacterial cell walls, improves the barrier function of intestinal epithelial cells.

PMID 22531915

[Mus musculus] Nod2 enhances the innate immune response of alveolar macrophages to Mycobacterium tuberculosis in human. (Demonstrated in human)

PMID 24163408

[Mus musculus] Nod1 and Nod2 synergize with Tlr4 in dendritic cells to increase IL12 production and enhance invariant natural killer T (iNKT) cell activation, and are important regulators of the IFN gamma response by iNKT cells during S. typhimurium and L. monocytogenes infections.

PMID 25423082

[Mus musculus] Salmonella enterica serovar Typhimurium �?msbB that possesses a modified lipid A triggers exacerbated colitis in the absence of Nod1 and/or Nod2, which is likely due to increased Tlr2 stimulation.

PMID 25817335

[Mus musculus] Nod2 regulates type-1 cytokine responses to Mycobacterium avium but is not required for the control of M. avium infection in vivo.

PMID 26444420

[Mus musculus] Leukotriene B4 acts on Nod2 pathway to enhance the immune response against influenza A infection.

Entrez Gene

Summary

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. [provided by RefSeq, Jul 2008]

Gene Information

Type

Protein coding

Genomic Location

Chromosome 16:50693603-50733077

Strand

Forward strand

Band

q12.1

Transcripts

ENST00000300589	ENSP00000300589
ENST00000526417
ENST00000531674	ENSP00000431681
ENST00000527070	ENSP00000435149
ENST00000532206
ENST00000534067	ENSP00000463145
ENST00000529633	ENSP00000462443
ENST00000524712	ENSP00000464065
ENST00000527052	ENSP00000463423
ENST00000534057	ENSP00000437246

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 86 experimentally validated interaction(s) in this database.
They are also associated with 5 interaction(s) predicted by orthology.

Experimentally validated
Total	86 [view]
Protein-Protein	83 [view]
Protein-DNA	3 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	5 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0019899	enzyme binding
GO:0019901	protein kinase binding
GO:0032500	muramyl dipeptide binding
GO:0042834	peptidoglycan binding
GO:0050700	CARD domain binding

Biological Process

GO:0000187	activation of MAPK activity
GO:0002224	toll-like receptor signaling pathway
GO:0002227	innate immune response in mucosa
GO:0002253	activation of immune response
GO:0002367	cytokine production involved in immune response
GO:0002381	immunoglobulin production involved in immunoglobulin mediated immune response
GO:0002606	positive regulation of dendritic cell antigen processing and presentation
GO:0002710	negative regulation of T cell mediated immunity
GO:0002732	positive regulation of dendritic cell cytokine production
GO:0002755	MyD88-dependent toll-like receptor signaling pathway
GO:0002756	MyD88-independent toll-like receptor signaling pathway
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: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:0007254	JNK cascade
GO:0007584	response to nutrient
GO:0008284	positive regulation of cell proliferation
GO:0009595	detection of biotic stimulus
GO:0016045	detection of bacterium
GO:0030277	maintenance of gastrointestinal epithelium
GO:0031398	positive regulation of protein ubiquitination
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: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:0032760	positive regulation of tumor necrosis factor production
GO:0032874	positive regulation of stress-activated MAPK cascade
GO:0034134	toll-like receptor 2 signaling pathway
GO:0034136	negative regulation of toll-like receptor 2 signaling pathway
GO:0034138	toll-like receptor 3 signaling pathway
GO:0034142	toll-like receptor 4 signaling pathway
GO:0034146	toll-like receptor 5 signaling pathway
GO:0034162	toll-like receptor 9 signaling pathway
GO:0034166	toll-like receptor 10 signaling pathway
GO:0035419	activation of MAPK activity involved in innate immune response
GO:0035556	intracellular signal transduction
GO:0035666	TRIF-dependent toll-like receptor signaling pathway
GO:0035872	nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway
GO:0038123	toll-like receptor TLR1:TLR2 signaling pathway
GO:0038124	toll-like receptor TLR6:TLR2 signaling pathway
GO:0042742	defense response to bacterium
GO:0042981	regulation of apoptotic process
GO:0043123	positive regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043330	response to exogenous dsRNA
GO:0043410	positive regulation of MAPK cascade
GO:0043552	positive regulation of phosphatidylinositol 3-kinase activity
GO:0044130	negative regulation of growth of symbiont in host
GO:0045087	innate immune response (InnateDB)
GO:0045089	positive regulation of innate immune response
GO:0045747	positive regulation of Notch signaling pathway
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
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:0050718	positive regulation of interleukin-1 beta secretion
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:0051259	protein oligomerization
GO:0051353	positive regulation of oxidoreductase activity
GO:0051403	stress-activated MAPK cascade
GO:0051770	positive regulation of nitric-oxide synthase biosynthetic process
GO:0060585	positive regulation of prostaglandin-endoperoxide synthase activity
GO:0070374	positive regulation of ERK1 and ERK2 cascade
GO:0070423	nucleotide-binding oligomerization domain containing signaling pathway
GO:0070431	nucleotide-binding oligomerization domain containing 2 signaling pathway
GO:0071224	cellular response to peptidoglycan
GO:0071225	cellular response to muramyl dipeptide
GO:0071407	cellular response to organic cyclic compound
GO:0071608	macrophage inflammatory protein-1 alpha production
GO:0090022	regulation of neutrophil chemotaxis
GO:2000110	negative regulation of macrophage apoptotic process
GO:2000363	positive regulation of prostaglandin-E synthase activity

Cellular Component

GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0005856	cytoskeleton
GO:0005886	plasma membrane
GO:0008180	COP9 signalosome
GO:0009986	cell surface
GO:0031982	vesicle
GO:0043234	protein complex