NOD2

NOD2
Identifiers
Aliases	NOD2, ACUG, BLAU, CARD15, CD, CLR16.3, IBD1, NLRC2, NOD2B, PSORAS1, nucleotide binding oligomerization domain containing 2
External IDs	MGI: 2429397 HomoloGene: 11156 GeneCards: NOD2
Genetically Related Diseases
Crohn's disease, inflammatory bowel disease[1]
Gene ontology Molecular function • Hsp90 protein binding • nucleotide binding • Hsp70 protein binding • protein binding • peptidoglycan binding • enzyme binding • actin binding • CARD domain binding • ATP binding • protein kinase binding • muramyl dipeptide binding Cellular component • cytoplasm • cytosol • vesicle • membrane • plasma membrane • protein complex • cell surface • basolateral plasma membrane • COP9 signalosome • cytoskeleton Biological process • positive regulation of prostaglandin-endoperoxide synthase activity • regulation of apoptotic process • defense response • detection of biotic stimulus • cytokine production involved in immune response • positive regulation of cytokine production involved in inflammatory response • intracellular signal transduction • detection of muramyl dipeptide • positive regulation of interleukin-10 production • positive regulation of epithelial cell proliferation • immune system process • positive regulation of oxidoreductase activity • response to muramyl dipeptide • positive regulation of prostaglandin-E synthase activity • positive regulation of JNK cascade • positive regulation of nitric-oxide synthase biosynthetic process • positive regulation of NIK/NF-kappaB signaling • positive regulation of phosphatidylinositol 3-kinase activity • positive regulation of gamma-delta T cell activation • cellular response to muramyl dipeptide • JNK cascade • negative regulation of macrophage apoptotic process • positive regulation of dendritic cell antigen processing and presentation • activation of MAPK activity • nucleotide-binding oligomerization domain containing 2 signaling pathway • maintenance of gastrointestinal epithelium • defense response to bacterium • positive regulation of NF-kappaB transcription factor activity • activation of MAPK activity involved in innate immune response • positive regulation of interleukin-8 production • positive regulation of interleukin-1 beta secretion • detection of bacterium • positive regulation of interleukin-1 beta production • regulation of inflammatory response • positive regulation of interleukin-6 production • protein oligomerization • positive regulation of tumor necrosis factor production • positive regulation of ERK1 and ERK2 cascade • positive regulation of I-kappaB kinase/NF-kappaB signaling • cytokine secretion involved in immune response • positive regulation of B cell activation • positive regulation of interleukin-17 production • positive regulation of type 2 immune response • nucleotide-binding oligomerization domain containing signaling pathway • positive regulation of stress-activated MAPK cascade • positive regulation of Notch signaling pathway • positive regulation of transcription from RNA polymerase II promoter • cellular response to organic cyclic compound • positive regulation of cell proliferation • innate immune response • response to nutrient • positive regulation of dendritic cell cytokine production Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	64127	257632
Ensembl	ENSG00000167207	ENSMUSG00000055994
UniProt	Q9HC29	Q8K3Z0
RefSeq (mRNA)	NM_001293557 NM_022162	NM_145857
RefSeq (protein)	NP_001280486.1 NP_071445.1	n/a
Location (UCSC)	Chr 16: 50.69 – 50.73 Mb	Chr 8: 88.65 – 88.69 Mb
PubMed search	[2]	[3]
Wikidata

View/Edit Human

View/Edit Mouse

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.^[4][5] NOD2 plays an important role in the immune system. It recognizes bacterial molecules (peptidoglycans) and stimulates an immune reaction.

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.^[6]

Structure

NOD2 protein model consisting two N-terminal CARD domains (red) connected via helical linker (blue) with central NOD domain (green). At C-terminus LRR domain (cyan) is located^[7]

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.^[8]

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.^[9]

Clinical significance

Mutations in this gene have been associated with Crohn's disease,^[7] Blau syndrome, severe pulmonary sarcoidosis ^[10] and Graft-versus-host disease.^[11]

The NOD2 gene is linked to inflammatory diseases such as Inflammatory bowel disease/Crohn's Disease and Blau syndrome.^[12][13]

Interactions

NOD2 has been shown to interact with NLRC4.^[14][15]

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.^[16]

See also

• Mifamurtide, a NOD2 activator for the treatment of osteosarcoma

References

1. "Diseases that are genetically associated with NOD2 view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. Gilberts EC, Greenstein AJ, Katsel P, Harpaz N, Greenstein RJ (Dec 1994). "Molecular evidence for two forms of Crohn disease". Proceedings of the National Academy of Sciences of the United States of America. 91 (26): 12721–4. doi:10.1073/pnas.91.26.12721. PMC 45511. PMID 7809109.
5. 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 (Feb 1996). "Mapping of a susceptibility locus for Crohn's disease on chromosome 16". Nature. 379 (6568): 821–3. doi:10.1038/379821a0. PMID 8587604.
6. Kufer TA, Banks DJ, Philpott DJ (Aug 2006). "Innate immune sensing of microbes by Nod proteins". Annals of the New York Academy of Sciences. 1072: 19–27. doi:10.1196/annals.1326.020. PMID 17057187.
7. Nakagome S, Mano S, Kozlowski L, Bujnicki JM, Shibata H, Fukumaki Y, Kidd JR, Kidd KK, Kawamura S, Oota H (Jun 2012). "Crohn's disease risk alleles on the NOD2 locus have been maintained by natural selection on standing variation". Molecular Biology and Evolution. 29 (6): 1569–85. doi:10.1093/molbev/mss006. PMC 3697811. PMID 22319155.
8. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G (Feb 2001). "Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB". The Journal of Biological Chemistry. 276 (7): 4812–8. doi:10.1074/jbc.M008072200. PMID 11087742.
9. "Entrez Gene: NOD2 nucleotide-binding oligomerization domain containing 2".
10. Sato H, Williams HR, Spagnolo P, Abdallah A, Ahmad T, Orchard TR, Copley SJ, Desai SR, Wells AU, du Bois RM, Welsh KI (Feb 2010). "CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis.". Eur Respir J. 35 (2): 324–30. doi:10.1183/09031936.00010209. PMID 19679608.
11. Zhao H, Jia M, Wang Z, Cheng Y, Luo Z, Chen Y, Xu X, Yang S, Tang Y (Jun 2015). "Association between NOD2 single nucleotide polymorphisms and Grade III-IV acute graft-versus-host disease: A meta-analysis". Hematology. 20 (5): 254–62. doi:10.1179/1607845414Y.0000000202. PMID 25248089.
12. Radford-Smith G, Pandeya N (Nov 2006). "Associations between NOD2/CARD15 genotype and phenotype in Crohn's disease--Are we there yet?". World Journal of Gastroenterology. 12 (44): 7097–103. PMID 17131470.
13. Kim TH, Payne U, Zhang X, Iwanaga Y, Davey MP, Rosenbaum JT, Inman RD (Jan 2007). "Altered host:pathogen interactions conferred by the Blau syndrome mutation of NOD2". Rheumatology International. 27 (3): 257–62. doi:10.1007/s00296-006-0250-0. PMID 17096091.
14. Damiano JS, Oliveira V, Welsh K, Reed JC (Jul 2004). "Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses". The Biochemical Journal. 381 (Pt 1): 213–9. doi:10.1042/BJ20031506. PMC 1133779. PMID 15107016.
15. Damiano JS, Stehlik C, Pio F, Godzik A, Reed JC (Jul 2001). "CLAN, a novel human CED-4-like gene". Genomics. 75 (1-3): 77–83. doi:10.1006/geno.2001.6579. PMID 11472070.
16. Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, Xiang Y, Bose S (Oct 2009). "Activation of innate immune antiviral responses by Nod2". Nature Immunology. 10 (10): 1073–80. doi:10.1038/ni.1782. PMC 2752345. PMID 19701189.

Further reading

• Punchard NA (Oct 2001). "Overview: Nod2, cause of, or contributor to, Crohn's disease". Current Opinion in Investigational Drugs. 2 (10): 1378–81. PMID 11890351.
• Satsangi J, Morecroft J, Shah NB, Nimmo E (Feb 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, Iwanaga Y, Kurz DE, Martin TM (Oct 2003). "With a mere nod, uveitis enters a new era". American Journal of Ophthalmology. 136 (4): 729–32. doi:10.1016/S0002-9394(03)00569-5. PMID 14516815.
• Kurokawa T, Kikuchi T, Ohta K, Imai H, Yoshimura N (Oct 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 (Dec 2003). "Lessons from Nod2 studies: towards a link between Crohn's disease and bacterial sensing". Trends in Immunology. 24 (12): 652–8. doi:10.1016/j.it.2003.10.007. PMID 14644139.
• Newman B, Siminovitch K (Dec 2003). "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 (2003). "IBD and genetics: new developments". Scandinavian Journal of Gastroenterology. Supplement. 38 (239): 63–8. doi:10.1080/00855920310002717. PMID 14743885.
• Kambe N, Nishikomori R, Kanazawa N (Aug 2005). "The cytosolic pattern-recognition receptor Nod2 and inflammatory granulomatous disorders". Journal of Dermatological Science. 39 (2): 71–80. doi:10.1016/j.jdermsci.2005.04.001. PMID 15927452.
• Newman B, Siminovitch KA (Jul 2005). "Recent advances in the genetics of inflammatory bowel disease". Current Opinion in Gastroenterology. 21 (4): 401–7. PMID 15930978.
• Martinon F, Tschopp J (Aug 2005). "NLRs join TLRs as innate sensors of pathogens". Trends in Immunology. 26 (8): 447–54. doi:10.1016/j.it.2005.06.004. PMID 15967716.
• Strober W, Murray PJ, Kitani A, Watanabe T (Jan 2006). "Signalling pathways and molecular interactions of NOD1 and NOD2". Nature Reviews. Immunology. 6 (1): 9–20. doi:10.1038/nri1747. PMID 16493424.
• Cavanaugh J (Jun 2006). "NOD2: ethnic and geographic differences". World Journal of Gastroenterology. 12 (23): 3673–7. PMID 16773683.
• Hugot JP (Aug 2006). "CARD15/NOD2 mutations in Crohn's disease". Annals of the New York Academy of Sciences. 1072 (1): 9–18. doi:10.1196/annals.1326.011. PMID 17057186.
• Vignal C, Singer E, Peyrin-Biroulet L, Desreumaux P, Chamaillard M (Apr 2007). "How NOD2 mutations predispose to Crohn's disease?". Microbes and Infection / Institut Pasteur. 9 (5): 658–63. doi:10.1016/j.micinf.2007.01.016. PMID 17379562.
• Quaglietta L, te Velde A, Staiano A, Troncone R, Hommes DW (May 2007). "Functional consequences of NOD2/CARD15 mutations in Crohn disease". Journal of Pediatric Gastroenterology and Nutrition. 44 (5): 529–39. doi:10.1097/MPG.0b013e31803815ee. PMID 17460484.
• van der Linde K, Boor PP, Houwing-Duistermaat JJ, Crusius BJ, Wilson PJ, Kuipers EJ, de Rooij FW (Jun 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.