NOD2

Nucleotide-binding oligomerization domain containing 2
Identifiers
Symbols	NOD2; ACUG; BLAU; CARD15; CD; CLR16.3; IBD1; NLRC2; NOD2B; PSORAS1
External IDs	OMIM: 605956 MGI: 2429397 HomoloGene: 11156 GeneCards: NOD2 Gene
Gene Ontology Molecular function • nucleotide binding • protein binding • ATP binding • enzyme binding • protein kinase binding • muramyl dipeptide binding • peptidoglycan binding • CARD domain binding Cellular component • cytoplasm • cytosol • cytosol • plasma membrane • signalosome • cell surface • vesicle Biological process • activation of MAPK activity • toll-like receptor signaling pathway • innate immune response in mucosa • activation of immune response • cytokine production involved in immune response • immunoglobulin production involved in immunoglobulin mediated immune response • positive regulation of dendritic cell antigen processing and presentation • negative regulation of T cell mediated immunity • MyD88-dependent toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • positive regulation of type 2 immune response • negative regulation of inflammatory response to antigenic stimulus • positive regulation of humoral immune response mediated by circulating immunoglobulin • defense response • positive regulation of biosynthetic process of antibacterial peptides active against Gram-positive bacteria • JNK cascade • Toll signaling pathway • detection of biotic stimulus • detection of bacterium • negative regulation of NF-kappaB transcription factor activity • response to muramyl dipeptide • response to lipopolysaccharide • detection of muramyl dipeptide • negative regulation of interferon-gamma production • negative regulation of interleukin-12 production • negative regulation of interleukin-18 production • negative regulation of interleukin-2 production • negative regulation of tumor necrosis factor production • positive regulation of interleukin-1 beta production • positive regulation of interleukin-10 production • positive regulation of interleukin-12 production • positive regulation of interleukin-17 production • positive regulation of interleukin-6 production • positive regulation of tumor necrosis factor production • positive regulation of tumor necrosis factor production • positive regulation of stress-activated MAPK cascade • toll-like receptor 1 signaling pathway • toll-like receptor 2 signaling pathway • negative regulation of toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • activation of MAPK activity involved in innate immune response • intracellular signal transduction • defense response to bacterium • regulation of apoptosis • positive regulation of I-kappaB kinase/NF-kappaB cascade • response to exogenous dsRNA • positive regulation of phosphatidylinositol 3-kinase activity • negative regulation of growth of symbiont in host • innate immune response • innate immune response • positive regulation of innate immune response • positive regulation of Notch signaling pathway • positive regulation of JNK cascade • positive regulation of gamma-delta T cell activation • positive regulation of epithelial cell proliferation • positive regulation of interleukin-1 beta secretion • regulation of inflammatory response • positive regulation of peptidyl-tyrosine phosphorylation • positive regulation of phagocytosis • defense response to Gram-positive bacterium • positive regulation of B cell activation • positive regulation of NF-kappaB transcription factor activity • positive regulation of NF-kappaB transcription factor activity • protein oligomerization • positive regulation of oxidoreductase activity • stress-activated MAPK cascade • positive regulation of nitric-oxide synthase biosynthetic process • positive regulation of prostaglandin-endoperoxide synthase activity • positive regulation of ERK1 and ERK2 cascade • nucleotide-binding oligomerization domain containing 2 signaling pathway • cellular response to peptidoglycan • macrophage inflammatory protein-1 alpha production • regulation of neutrophil chemotaxis • negative regulation of macrophage apoptosis • positive regulation of prostaglandin-E synthase activity Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	64127	257632
Ensembl	ENSG00000167207	ENSMUSG00000055994
UniProt	Q9HC29	Q2PZA3
RefSeq (mRNA)	NM_022162.1	NM_145857.2
RefSeq (protein)	NP_071445.1	NP_665856.2
Location (UCSC)	Chr 16: 50.73 – 50.77 Mb	Chr 8: 91.17 – 91.21 Mb
PubMed search	[1]	[2]

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) also known as caspase recruitment domain-containing protein 15 (CARD15) or inflammatory bowel disease protein 1 (IBD1) is a protein that in humans is encoded by the NOD2 gene located on chromosome 16.^[1][2] NOD2 plays an important role in the immune system. It recognizes bacterial molecules (peptidoglycans) and stimulates an immune reaction. Mutations in NOD2 are associated with autoimmune diseases.

NOD2 is an intracellular pattern recognition receptor, which is similar in structure to resistant proteins of plants and recognizes molecules containing the specific structure called muramyl dipeptide (MDP) that is found in certain bacteria.^[3]

Structure

The C-terminal portion of the protein contains a leucine-rich repeat domain that is known to play a role in protein–protein interactions. The middle part of the protein is characterized by a NOD domain involved in protein self-oligomerization. The N-terminal portion contains two CARD domains known to play a role in apoptosis and NF-κB activation pathways.^[4]

Function

This gene is a member of the NOD1/Apaf-1 family (also known as NOD-like receptor family) and encodes a protein with two caspase recruitment domains (CARDs) and eleven leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response by recognizing the bacterial molecules which possess the muramyl dipeptide (MDP) moiety and activating the NF-κB protein.^[5] and graft-versus-host disease.

Clinical significance

Mutations in this gene have been associated with Crohn's disease and Blau syndrome.^[5] and graft-versus-host disease.

The NOD2 gene is linked to inflammatory diseases such as inflammatory bowel disease/Crohn's Disease and Blau syndrome.^[6][7]

Interactions

NOD2 has been shown to interact with NLRC4.^[8][9]

NOD2 has also been shown to bind to MAVS in response to ssRNA or viral RNA treatment and activate the IFN response. This is the first report of NOD2 acting as a pattern-recognition receptor for viruses.^[10]

See also

• Mifamurtide, a NOD2 activator for the treatment of osteosarcoma

References

1. ^ Gilberts EC, Greenstein AJ, Katsel P, Harpaz N, Greenstein RJ (December 1994). "Molecular evidence for two forms of Crohn disease". Proc. Natl. Acad. Sci. U.S.A. 91 (26): 12721–4. PMC 45511. PMID 7809109. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=45511. 
2. ^ Hugot JP, Laurent-Puig P, Gower-Rousseau C, Olson JM, Lee JC, Beaugerie L, Naom I, Dupas JL, Van Gossum A, Orholm M, Bonaiti-Pellie C, Weissenbach J, Mathew CG, Lennard-Jones JE, Cortot A, Colombel JF, Thomas G (February 1996). "Mapping of a susceptibility locus for Crohn's disease on chromosome 16". Nature 379 (6568): 821–3. doi:10.1038/379821a0. PMID 8587604. 
3. ^ Kufer TA, Banks DJ, Philpott DJ (August 2006). "Innate immune sensing of microbes by Nod proteins". Ann. N. Y. Acad. Sci. 1072: 19–27. doi:10.1196/annals.1326.020. PMID 17057187. 
4. ^ Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G (February 2001). "Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB". J. Biol. Chem. 276 (7): 4812–8. doi:10.1074/jbc.M008072200. PMID 11087742. 
5. ^ ^{a b} "Entrez Gene: NOD2 nucleotide-binding oligomerization domain containing 2". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=64127. 
6. ^ Radford-Smith G, Pandeya N (November 2006). "Associations between NOD2/CARD15 genotype and phenotype in Crohn's disease--Are we there yet?". World J. Gastroenterol. 12 (44): 7097–103. PMID 17131470. 
7. ^ Kim TH, Payne U, Zhang X, Iwanaga Y, Davey MP, Rosenbaum JT, Inman RD (January 2007). "Altered host:pathogen interactions conferred by the Blau syndrome mutation of NOD2". Rheumatol. Int. 27 (3): 257–62. doi:10.1007/s00296-006-0250-0. PMID 17096091. 
8. ^ Damiano JS, Oliveira V, Welsh K, Reed JC (July 2004). "Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses". Biochem. J. 381 (Pt 1): 213–9. doi:10.1042/BJ20031506. PMC 1133779. PMID 15107016. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1133779. 
9. ^ Damiano JS, Stehlik C, Pio F, Godzik A, Reed JC (July 2001). "CLAN, a novel human CED-4-like gene". Genomics 75 (1-3): 77–83. doi:10.1006/geno.2001.6579. PMID 11472070. 
10. ^ Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, Xiang Y, Bose S (August 2009). "Activation of innate immune antiviral responses by Nod2". Nat. Immunol. 10 (10): 1073–80. doi:10.1038/ni.1782. PMC 2752345. PMID 19701189. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2752345. 

Further reading

• Punchard NA (2002). "Overview: Nod2, cause of, or contributor to, Crohn's disease.". Current opinion in investigational drugs (London, England : 2000) 2 (10): 1378–81. PMID 11890351. 
• Satsangi J, Morecroft J, Shah NB, Nimmo E (2003). "Genetics of inflammatory bowel disease: scientific and clinical implications.". Best practice & research. Clinical gastroenterology 17 (1): 3–18. doi:10.1053/bega.2002.0349. PMID 12617879. 
• Rosenbaum JT, Planck SR, Davey MP, et al. (2003). "With a mere nod, uveitis enters a new era.". Am. J. Ophthalmol. 136 (4): 729–32. doi:10.1016/S0002-9394(03)00569-5. PMID 14516815. 
• Kurokawa T, Kikuchi T, Ohta K, et al. (2003). "Ocular manifestations in Blau syndrome associated with a CARD15/Nod2 mutation.". Ophthalmology 110 (10): 2040–4. doi:10.1016/S0161-6420(03)00717-6. PMID 14522785. 
• Girardin SE, Hugot JP, Sansonetti PJ (2004). "Lessons from Nod2 studies: towards a link between Crohn's disease and bacterial sensing.". Trends Immunol. 24 (12): 652–8. doi:10.1016/j.it.2003.10.007. PMID 14644139. 
• Newman B, Siminovitch K (2004). "Inflammatory bowel disease: Crohn's disease and the success of NODern genetics.". Clinical and investigative medicine. Médecine clinique et experimentale 26 (6): 303–14. PMID 14690304. 
• Oostenbrug LE, van Dullemen HM, te Meerman GJ, Jansen PL (2004). "IBD and genetics: new developments.". Scand. J. Gastroenterol. Suppl. (239): 63–8. PMID 14743885. 
• Kambe N, Nishikomori R, Kanazawa N (2005). "The cytosolic pattern-recognition receptor Nod2 and inflammatory granulomatous disorders.". J. Dermatol. Sci. 39 (2): 71–80. doi:10.1016/j.jdermsci.2005.04.001. PMID 15927452. 
• Newman B, Siminovitch KA (2005). "Recent advances in the genetics of inflammatory bowel disease.". Curr. Opin. Gastroenterol. 21 (4): 401–7. PMID 15930978. 
• Martinon F, Tschopp J (2006). "NLRs join TLRs as innate sensors of pathogens.". Trends Immunol. 26 (8): 447–54. doi:10.1016/j.it.2005.06.004. PMID 15967716. 
• Strober W, Murray PJ, Kitani A, Watanabe T (2006). "Signalling pathways and molecular interactions of NOD1 and NOD2.". Nat. Rev. Immunol. 6 (1): 9–20. doi:10.1038/nri1747. PMID 16493424. 
• Cavanaugh J (2006). "NOD2: ethnic and geographic differences.". World J. Gastroenterol. 12 (23): 3673–7. PMID 16773683. 
• Hugot JP (2006). "CARD15/NOD2 mutations in Crohn's disease.". Ann. N. Y. Acad. Sci. 1072 (1): 9–18. doi:10.1196/annals.1326.011. PMID 17057186. 
• Vignal C, Singer E, Peyrin-Biroulet L, et al. (2007). "How NOD2 mutations predispose to Crohn's disease?". Microbes Infect. 9 (5): 658–63. doi:10.1016/j.micinf.2007.01.016. PMID 17379562. 
• Quaglietta L, te Velde A, Staiano A, et al. (2007). "Functional consequences of NOD2/CARD15 mutations in Crohn disease.". J. Pediatr. Gastroenterol. Nutr. 44 (5): 529–39. doi:10.1097/MPG.0b013e31803815ee. PMID 17460484. 
• van der Linde K, Boor PP, Houwing-Duistermaat JJ, et al. (2007). "CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of European studies.". European journal of gastroenterology & hepatology 19 (6): 449–59. doi:10.1097/01.meg.0000236887.44214.6a. PMID 17489054.