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Nucleotide-binding oligomerization domain containing 2
External IDs OMIM605956 MGI2429397 HomoloGene11156 ChEMBL: 1293266 GeneCards: NOD2 Gene
RNA expression pattern
PBB GE NOD2 220066 at tn.png
More reference expression data
Species Human Mouse
Entrez 64127 257632
Ensembl ENSG00000167207 ENSMUSG00000055994
UniProt Q9HC29 Q8K3Z0
RefSeq (mRNA) NM_001293557 NM_145857
RefSeq (protein) NP_001280486 NP_665856
Location (UCSC) Chr 16:
50.69 – 50.73 Mb
Chr 8:
88.65 – 88.69 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.

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]


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[4]

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.[5]


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.[6]

Clinical significance[edit]

Mutations in this gene have been associated with Crohn's disease[4] and Blau syndrome[6] and graft-versus-host disease.[7]

The NOD2 gene is linked to inflammatory diseases such as inflammatory bowel disease/Crohn's Disease and Blau syndrome.[8][9]


NOD2 has been shown to interact with NLRC4.[10][11]

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.[12]

See also[edit]


  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. doi:10.1073/pnas.91.26.12721. PMC 45511. PMID 7809109. 
  2. ^ Hugot JP, Laurent-Puig P, Gower-Rousseau C, Olson JM, Lee JC, Beaugerie L et al. (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. ^ a b Nakagome, S; Mano, S; Kozlowski, L; Bujnicki, J. M.; Shibata, H; Fukumaki, Y; Kidd, J. R.; Kidd, K. K.; Kawamura, S; Oota, H (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.  edit
  5. ^ 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. 
  6. ^ a b "Entrez Gene: NOD2 nucleotide-binding oligomerization domain containing 2". 
  7. ^ Zhao H, Jia M, Wang Z, Cheng Y, Luo Z, Chen Y et al. (2014). "Association between NOD2 single nucleotide polymorphisms and Grade III-IV acute graft-versus-host disease: A meta-analysis". Hematology. doi:10.1179/1607845414Y.0000000202. PMID 25248089. 
  8. ^ 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. 
  9. ^ Kim TH, Payne U, Zhang X, Iwanaga Y, Davey MP, Rosenbaum JT et al. (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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH et al. (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. 

Further reading[edit]

  • Punchard NA (2001). "Overview: Nod2, cause of, or contributor to, Crohn's disease". Curr Opin Investig Drugs 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 Pract Res Clin Gastroenterol 17 (1): 3–18. doi:10.1053/bega.2002.0349. PMID 12617879. 
  • Rosenbaum JT, Planck SR, Davey MP, Iwanaga Y, Kurz DE, Martin TM (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, Imai H, Yoshimura N (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 (2003). "Lessons from Nod2 studies: towards a link between Crohn's disease and bacterial sensing". Trends Immunol. 24 (12): 652–8. doi:10.1016/ PMID 14644139. 
  • Newman B, Siminovitch K (2003). "Inflammatory bowel disease: Crohn's disease and the success of NODern genetics". Clin Invest Med 26 (6): 303–14. PMID 14690304. 
  • Oostenbrug LE, van Dullemen HM, te Meerman GJ, Jansen PL (2003). "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 (2005). "NLRs join TLRs as innate sensors of pathogens". Trends Immunol. 26 (8): 447–54. doi:10.1016/ 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, Desreumaux P, Chamaillard M (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, Troncone R, Hommes DW (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, Crusius BJ, Wilson PJ, Kuipers EJ et al. (2007). "CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of European studies". Eur J Gastroenterol Hepatol 19 (6): 449–59. doi:10.1097/01.meg.0000236887.44214.6a. PMID 17489054.