NOD2 explained

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.^[3]

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.^[4]

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.^[5]

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.^[6]

Clinical significance

Mutations in this gene have been associated with serious autoimmune diseases like Crohn's disease, Blau syndrome, pulmonary sarcoidosis^[7] and Graft-versus-host disease.^{[8] [9] [10]}

Interactions

NOD2 has been shown to interact with NLRC4.^{[11] [12]}

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.^[13]

See also

• Mifamurtide, a NOD2 activator for the treatment of osteosarcoma

Further reading

• Punchard NA . Overview: Nod2, cause of, or contributor to, Crohn's disease . Current Opinion in Investigational Drugs . 2 . 10 . 1378–81 . Oct 2001 . 11890351 .
• Satsangi J, Morecroft J, Shah NB, Nimmo E . Genetics of inflammatory bowel disease: scientific and clinical implications . Best Practice & Research. Clinical Gastroenterology . 17 . 1 . 3–18 . Feb 2003 . 12617879 . 10.1053/bega.2002.0349 .
• Rosenbaum JT, Planck SR, Davey MP, Iwanaga Y, Kurz DE, Martin TM . With a mere nod, uveitis enters a new era . American Journal of Ophthalmology . 136 . 4 . 729–32 . Oct 2003 . 14516815 . 10.1016/S0002-9394(03)00569-5 .
• Kurokawa T, Kikuchi T, Ohta K, Imai H, Yoshimura N . Ocular manifestations in Blau syndrome associated with a CARD15/Nod2 mutation . Ophthalmology . 110 . 10 . 2040–4 . Oct 2003 . 14522785 . 10.1016/S0161-6420(03)00717-6 .
• Girardin SE, Hugot JP, Sansonetti PJ . Lessons from Nod2 studies: towards a link between Crohn's disease and bacterial sensing . Trends in Immunology . 24 . 12 . 652–8 . Dec 2003 . 14644139 . 10.1016/j.it.2003.10.007 .
• Newman B, Siminovitch K . Inflammatory bowel disease: Crohn's disease and the success of NODern genetics . Clinical and Investigative Medicine . 26 . 6 . 303–14 . Dec 2003 . 14690304 .
• Oostenbrug LE, van Dullemen HM, te Meerman GJ, Jansen PL . IBD and genetics: new developments . Scandinavian Journal of Gastroenterology. Supplement . 38. 239 . 63–8 . 2003 . 14743885 . 10.1080/00855920310002717. 1 November 2024 .
• Kambe N, Nishikomori R, Kanazawa N . The cytosolic pattern-recognition receptor Nod2 and inflammatory granulomatous disorders . Journal of Dermatological Science . 39 . 2 . 71–80 . Aug 2005 . 15927452 . 10.1016/j.jdermsci.2005.04.001 .
• Newman B, Siminovitch KA . Recent advances in the genetics of inflammatory bowel disease . Current Opinion in Gastroenterology . 21 . 4 . 401–7 . Jul 2005 . 15930978 .
• Martinon F, Tschopp J . NLRs join TLRs as innate sensors of pathogens . Trends in Immunology . 26 . 8 . 447–54 . Aug 2005 . 15967716 . 10.1016/j.it.2005.06.004 .
• Strober W, Murray PJ, Kitani A, Watanabe T . Signalling pathways and molecular interactions of NOD1 and NOD2 . Nature Reviews. Immunology . 6 . 1 . 9–20 . Jan 2006 . 16493424 . 10.1038/nri1747 . 33505741 .
• Cavanaugh J . NOD2: ethnic and geographic differences . World Journal of Gastroenterology . 12 . 23 . 3673–7 . Jun 2006 . 16773683 . 10.3748/wjg.v12.i23.3673 . 4087459 . free .
• Hugot JP . CARD15/NOD2 mutations in Crohn's disease . Annals of the New York Academy of Sciences . 1072 . 1 . 9–18 . Aug 2006 . 17057186 . 10.1196/annals.1326.011 . 2006NYASA1072....9H . 24150549 .
• Vignal C, Singer E, Peyrin-Biroulet L, Desreumaux P, Chamaillard M . How NOD2 mutations predispose to Crohn's disease? . Microbes and Infection / Institut Pasteur . 9 . 5 . 658–63 . Apr 2007 . 17379562 . 10.1016/j.micinf.2007.01.016 . free .
• Quaglietta L, te Velde A, Staiano A, Troncone R, Hommes DW . Functional consequences of NOD2/CARD15 mutations in Crohn disease . Journal of Pediatric Gastroenterology and Nutrition . 44 . 5 . 529–39 . May 2007 . 17460484 . 10.1097/MPG.0b013e31803815ee . 37476303 . free .
• van der Linde K, Boor PP, Houwing-Duistermaat JJ, Crusius BJ, Wilson PJ, Kuipers EJ, de Rooij FW . 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 . Jun 2007 . 17489054 . 10.1097/01.meg.0000236887.44214.6a . 17766170 .

Notes and References

1. Gilberts EC, Greenstein AJ, Katsel P, Harpaz N, Greenstein RJ . 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 . Dec 1994 . 7809109 . 45511 . 10.1073/pnas.91.26.12721 . 1994PNAS...9112721G . free .
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 . Mapping of a susceptibility locus for Crohn's disease on chromosome 16 . Nature . 379 . 6568 . 821–3 . Feb 1996 . 8587604 . 10.1038/379821a0 . 1996Natur.379..821H . 4311407 .
3. Mahla RS, Reddy MC, Prasad DV, Kumar H . Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology . Frontiers in Immunology . 4 . 248 . September 2013 . 24032031 . 3759294 . 10.3389/fimmu.2013.00248 . free .
4. Kufer TA, Banks DJ, Philpott DJ . Innate immune sensing of microbes by Nod proteins . Annals of the New York Academy of Sciences . 1072 . 19–27 . Aug 2006 . 1 . 17057187 . 10.1196/annals.1326.020 . 2006NYASA1072...19K . 20217610 .
5. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G . 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 . Feb 2001 . 11087742 . 10.1074/jbc.M008072200 . free .
6. Web site: Entrez Gene: NOD2 nucleotide-binding oligomerization domain containing 2.
7. Sato H, Williams HR, Spagnolo P, Abdallah A, Ahmad T, Orchard TR, Copley SJ, Desai SR, Wells AU, du Bois RM, Welsh KI . CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis.. Eur Respir J . 35 . 2 . 324–30 . Feb 2010 . 19679608 . 10.1183/09031936.00010209. free .
8. Zhao H, Jia M, Wang Z, Cheng Y, Luo Z, Chen Y, Xu X, Yang S, Tang Y . Association between NOD2 single nucleotide polymorphisms and Grade III-IV acute graft-versus-host disease: A meta-analysis . Hematology . 20 . 5 . 254–62 . Jun 2015 . 25248089 . 10.1179/1607845414Y.0000000202 . 206850232 . free .
9. Radford-Smith G, Pandeya N . Associations between NOD2/CARD15 genotype and phenotype in Crohn's disease--Are we there yet? . World Journal of Gastroenterology . 12 . 44 . 7097–103 . Nov 2006 . 17131470 . 10.3748/wjg.v12.i44.7097 . 4087769 . free .
10. Kim TH, Payne U, Zhang X, Iwanaga Y, Davey MP, Rosenbaum JT, Inman RD . Altered host:pathogen interactions conferred by the Blau syndrome mutation of NOD2 . Rheumatology International . 27 . 3 . 257–62 . Jan 2007 . 17096091 . 10.1007/s00296-006-0250-0 . 23739992 .
11. Damiano JS, Oliveira V, Welsh K, Reed JC . Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses . The Biochemical Journal . 381 . Pt 1 . 213–9 . Jul 2004 . 15107016 . 1133779 . 10.1042/BJ20031506 .
12. Damiano JS, Stehlik C, Pio F, Godzik A, Reed JC . CLAN, a novel human CED-4-like gene . Genomics . 75 . 1–3 . 77–83 . Jul 2001 . 11472070 . 10.1006/geno.2001.6579 .
13. Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, Xiang Y, Bose S . Activation of innate immune antiviral responses by Nod2 . Nature Immunology . 10 . 10 . 1073–80 . Oct 2009 . 19701189 . 2752345 . 10.1038/ni.1782 .