同: CARD15

同: CARD15

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/06/27 20:46:04」(JST)

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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]

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^[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]

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 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]

Interactions

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]

References

^ 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.
^ 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.
^ 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.
^ ^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
^ 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.
^ ^a ^b "Entrez Gene: NOD2 nucleotide-binding oligomerization domain containing 2".
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.

UpToDate Contents

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1. 炎症性腸疾患における遺伝的要因 genetic factors in inflammatory bowel disease
2. 炎症性腸疾患の病因における免疫および微生物学的機序 immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease
3. 移植片対宿主病の病因 pathogenesis of graft versus host disease
4. 自然免疫系の概要 an overview of the innate immune system
5. 乾癬性関節炎の病因 pathogenesis of psoriatic arthritis

English Journal

Immunobiotic Lactobacillus administered post-exposure averts the lethal sequelae of respiratory virus infection.

Percopo CM1, Rice TA1, Brenner TA1, Dyer KD1, Luo JL1, Kanakabandi K2, Sturdevant DE2, Porcella SF2, Domachowske JB3, Keicher JD4, Rosenberg HF5.
Antiviral research.Antiviral Res.2015 Sep;121:109-19. doi: 10.1016/j.antiviral.2015.07.001. Epub 2015 Jul 2.
We reported previously that priming of the respiratory tract with immunobiotic Lactobacillus prior to virus challenge protects mice against subsequent lethal infection with pneumonia virus of mice (PVM). We present here the results of gene microarray which document differential expression of proinfl
PMID 26145728

miRNA-regulated gene expression differs in celiac disease patients according to the age of presentation.

Buoli Comani G1, Panceri R, Dinelli M, Biondi A, Mancuso C, Meneveri R, Barisani D.
Genes & nutrition.Genes Nutr.2015 Sep;10(5):482. doi: 10.1007/s12263-015-0482-2. Epub 2015 Aug 2.
Celiac disease is an intestinal disease which shows different symptoms and clinical manifestations among pediatric and adult patients. These variations could be imputable to age-related changes in gut architecture and intestinal immune system, which could be characterized by gene expression differen
PMID 26233308

Genetic Variation in Pattern Recognition Receptors and Adaptor Proteins Associated With Development of Chronic Q Fever.

Schoffelen T1, Ammerdorffer A1, Hagenaars JC2, Bleeker-Rovers CP1, Wegdam-Blans MC3, Wever PC4, Joosten LA1, van der Meer JW1, Sprong T5, Netea MG1, van Deuren M1, van de Vosse E6.
The Journal of infectious diseases.J Infect Dis.2015 Sep 1;212(5):818-29. doi: 10.1093/infdis/jiv113. Epub 2015 Feb 26.
BACKGROUND: Q fever is an infection caused by Coxiella burnetii. Persistent infection (chronic Q fever) develops in 1%-5% of patients. We hypothesize that inefficient recognition of C. burnetii and/or activation of host-defense in individuals carrying genetic variants in pattern recognition receptor
PMID 25722298

Japanese Journal

皮膚と自己炎症性機序による肉芽腫性疾患 (AYUMI 皮膚免疫学 : 免疫臓器としての意義と病態)

中野倫代,神戸直智
医学のあゆみ 242(10), 791-794, 2012-09-08
NAID 40019398229

NOD2変異からみたCrohn病の発症機序 (AYUMI 消化器疾患と自然免疫 : 腸管免疫制御機構における自然免疫とIBD)

渡邉智裕,千葉勉
医学のあゆみ 241(3), 191-195, 2012-04-21
NAID 40019222432

細菌由来複合糖質の合成と自然免疫研究

深瀬浩一,藤本ゆかり,下山敦史,田中克典
有機合成化学協会誌 70(2), 113-130, 2012-02-01
… Intracellular peptidoglycan receptors, 'Nod1' and 'Nod2', and their ligand structures were identified by using synthetic peptidoglycan partial structures. …
NAID 10030481197

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★リンクテーブル★

「NO」

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 IUPHAR: 1763 ChEMBL: 1293266 GeneCards: NOD2 Gene
Gene ontology
Molecular function	• protein binding; • ATP binding; • enzyme binding; • protein kinase binding; • muramyl dipeptide binding; • peptidoglycan binding; • CARD domain binding;
Cellular component	• cytoplasm; • cytosol; • cytoskeleton; • plasma membrane; • COP9 signalosome; • cell surface; • vesicle; • protein complex;
Biological process	• activation of MAPK activity; • toll-like receptor signaling pathway; • innate immune response in mucosa; • microglial cell activation involved in 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; • positive regulation of dendritic cell cytokine production; • MyD88-dependent 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; • response to nutrient; • detection of biotic stimulus; • detection of bacterium; • maintenance of gastrointestinal epithelium; • 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 stress-activated MAPK cascade; • 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; • toll-like receptor 5 signaling pathway; • toll-like receptor 9 signaling pathway; • toll-like receptor 10 signaling pathway; • activation of MAPK activity involved in innate immune response; • intracellular signal transduction; • TRIF-dependent toll-like receptor signaling pathway; • nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway; • toll-like receptor TLR1:TLR2 signaling pathway; • toll-like receptor TLR6:TLR2 signaling pathway; • defense response to bacterium; • positive regulation of I-kappaB kinase/NF-kappaB signaling; • response to exogenous dsRNA; • positive regulation of phosphatidylinositol 3-kinase activity; • negative regulation of growth of symbiont in host; • innate immune response; • positive regulation of Notch signaling pathway; • positive regulation of transcription from RNA polymerase II promoter; • 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; • protein oligomerization; • positive regulation of oxidoreductase activity; • stress-activated MAPK cascade; • positive regulation of nitric-oxide synthase biosynthetic process; • pathogen-associated molecular pattern dependent induction by symbiont of host innate immune response; • positive regulation of prostaglandin-endoperoxide synthase activity; • positive regulation of ERK1 and ERK2 cascade; • nucleotide-binding oligomerization domain containing signaling pathway; • nucleotide-binding oligomerization domain containing 2 signaling pathway; • cellular response to peptidoglycan; • cellular response to muramyl dipeptide; • macrophage inflammatory protein-1 alpha production; • regulation of neutrophil chemotaxis; • negative regulation of macrophage apoptotic process; • positive regulation of prostaglandin-E synthase activity;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

　　[★] 一酸化窒素 nitrogen oxide nitric oxide

[pmid7809109-1] 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.

[pmid8587604-2] 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.

[pmid17057187-3] 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.

[pmid22319155-4] 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

[pmid11087742-5] 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.

[entrez-6] "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.

[pmid17131470-8] 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.

[pmid17096091-9] 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.

[pmid15107016-10] 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.

[pmid11472070-11] 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.

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NOD2