NOD2

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.{{cite journal | vauthors = Gilberts EC, Greenstein AJ, Katsel P, Harpaz N, Greenstein RJ | title = Molecular evidence for two forms of Crohn disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 26 | pages = 12721–4 | date = Dec 1994 | pmid = 7809109 | pmc = 45511 | doi = 10.1073/pnas.91.26.12721 | bibcode = 1994PNAS...9112721G | doi-access = free }}{{cite journal | vauthors = 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 | title = Mapping of a susceptibility locus for Crohn's disease on chromosome 16 | journal = Nature | volume = 379 | issue = 6568 | pages = 821–3 | date = Feb 1996 | pmid = 8587604 | doi = 10.1038/379821a0 | bibcode = 1996Natur.379..821H | s2cid = 4311407 }} NOD2 plays an important role in the immune system. It recognizes bacterial molecules (peptidoglycans) and stimulates an immune reaction.{{cite journal | vauthors = Mahla RS, Reddy MC, Prasad DV, Kumar H | title = Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology | journal = Frontiers in Immunology | volume = 4 | pages = 248 | date = September 2013 | pmid = 24032031 | pmc = 3759294 | doi = 10.3389/fimmu.2013.00248 | doi-access = free }}

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.{{cite journal | vauthors = Kufer TA, Banks DJ, Philpott DJ | title = Innate immune sensing of microbes by Nod proteins | journal = Annals of the New York Academy of Sciences | volume = 1072 | pages = 19–27 | date = Aug 2006 | issue = 1 | pmid = 17057187 | doi = 10.1196/annals.1326.020 | bibcode = 2006NYASA1072...19K | s2cid = 20217610 }}

Structure

Image:Nod2 protein.png

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.{{cite journal | vauthors = Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G | title = Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB | journal = The Journal of Biological Chemistry | volume = 276 | issue = 7 | pages = 4812–8 | date = Feb 2001 | pmid = 11087742 | doi = 10.1074/jbc.M008072200 | doi-access = free }}

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.{{cite web | title = Entrez Gene: NOD2 nucleotide-binding oligomerization domain containing 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=64127}}

Clinical significance

Mutations in this gene have been associated with serious autoimmune diseases like Crohn's disease, Blau syndrome, pulmonary sarcoidosis{{cite journal | vauthors = Sato H, Williams HR, Spagnolo P, Abdallah A, Ahmad T, Orchard TR, Copley SJ, Desai SR, Wells AU, du Bois RM, Welsh KI | title = CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis.| journal = Eur Respir J | volume = 35 | issue = 2 | pages = 324–30 | date = Feb 2010 | pmid = 19679608 | doi = 10.1183/09031936.00010209| doi-access = free }} and Graft-versus-host disease.{{cite journal | vauthors = Zhao H, Jia M, Wang Z, Cheng Y, Luo Z, Chen Y, Xu X, Yang S, Tang Y | title = Association between NOD2 single nucleotide polymorphisms and Grade III-IV acute graft-versus-host disease: A meta-analysis | journal = Hematology | volume = 20 | issue = 5 | pages = 254–62 | date = Jun 2015 | pmid = 25248089 | doi = 10.1179/1607845414Y.0000000202 | s2cid = 206850232 | doi-access = free }}{{cite journal | vauthors = Radford-Smith G, Pandeya N | title = Associations between NOD2/CARD15 genotype and phenotype in Crohn's disease--Are we there yet? | journal = World Journal of Gastroenterology | volume = 12 | issue = 44 | pages = 7097–103 | date = Nov 2006 | pmid = 17131470 | doi = 10.3748/wjg.v12.i44.7097 | pmc = 4087769 | doi-access = free }}{{cite journal | vauthors = Kim TH, Payne U, Zhang X, Iwanaga Y, Davey MP, Rosenbaum JT, Inman RD | title = Altered host:pathogen interactions conferred by the Blau syndrome mutation of NOD2 | journal = Rheumatology International | volume = 27 | issue = 3 | pages = 257–62 | date = Jan 2007 | pmid = 17096091 | doi = 10.1007/s00296-006-0250-0 | s2cid = 23739992 }}

Interactions

NOD2 has been shown to interact with NLRC4.{{cite journal | vauthors = Damiano JS, Oliveira V, Welsh K, Reed JC | title = Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses | journal = The Biochemical Journal | volume = 381 | issue = Pt 1 | pages = 213–9 | date = Jul 2004 | pmid = 15107016 | pmc = 1133779 | doi = 10.1042/BJ20031506 }}{{cite journal | vauthors = Damiano JS, Stehlik C, Pio F, Godzik A, Reed JC | title = CLAN, a novel human CED-4-like gene | journal = Genomics | volume = 75 | issue = 1–3 | pages = 77–83 | date = Jul 2001 | pmid = 11472070 | doi = 10.1006/geno.2001.6579 }}

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.{{cite journal | vauthors = Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, Xiang Y, Bose S | title = Activation of innate immune antiviral responses by Nod2 | journal = Nature Immunology | volume = 10 | issue = 10 | pages = 1073–80 | date = Oct 2009 | pmid = 19701189 | pmc = 2752345 | doi = 10.1038/ni.1782 }}

NOD2

Structure

Function

Clinical significance

Interactions

See also

References

Further reading