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HMDB Protein ID HMDBP13949
Secondary Accession Numbers None
Name Nucleotide-binding oligomerization domain-containing protein 2
  1. Caspase recruitment domain-containing protein 15
  2. Inflammatory bowel disease protein 1
Gene Name NOD2
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function Involved in gastrointestinal immunity. Upon stimulation by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, binds the proximal adapter receptor-interacting RIPK2, which recruits ubiquitin ligases as XIAP, BIRC2, BIRC3, INAVA and the LUBAC complex, triggering activation of MAP kinases and activation of NF-kappa-B signaling. This in turn leads to the transcriptional activation of hundreds of genes involved in immune response. Required for MDP-induced NLRP1-dependent CASP1 activation and IL1B release in macrophages (PubMed:18511561). Component of an autophagy-mediated antibacterial pathway together with ATG16L1 (PubMed:20637199). Plays also a role in sensing single-stranded RNA (ssRNA) from viruses. Interacts with mitochondrial antiviral signaling/MAVS, leading to activation of interferon regulatory factor-3/IRF3 and expression of type I interferon (PubMed:19701189).
  • Inflammatory bowel disease
  • NOD-like receptor signaling pathway
  • TNF signaling pathway
  • Tuberculosis
Reactions Not Available
GO Classification
Biological Process
positive regulation of innate immune response
negative regulation of inflammatory response to antigenic stimulus
regulation of inflammatory response
cellular response to muramyl dipeptide
detection of biotic stimulus
detection of muramyl dipeptide
maintenance of gastrointestinal epithelium
negative regulation of interleukin-18 production
negative regulation of T cell mediated immunity
positive regulation of biosynthetic process of antibacterial peptides active against Gram-positive bacteria
positive regulation of dendritic cell antigen processing and presentation
detection of bacterium
positive regulation of interleukin-10 production
positive regulation of gamma-delta T cell activation
positive regulation of prostaglandin-E synthase activity
negative regulation of interferon-gamma production
positive regulation of interleukin-8 production
positive regulation of prostaglandin-endoperoxide synthase activity
positive regulation of protein K63-linked ubiquitination
positive regulation of xenophagy
regulation of neutrophil chemotaxis
response to muramyl dipeptide
defense response to bacterium
positive regulation of phosphatidylinositol 3-kinase activity
positive regulation of B cell activation
negative regulation of tumor necrosis factor production
positive regulation of interleukin-12 production
positive regulation of type 2 immune response
response to exogenous dsRNA
positive regulation of nitric-oxide synthase biosynthetic process
response to nutrient
interleukin-1-mediated signaling pathway
positive regulation of interleukin-17 production
positive regulation of phagocytosis
cellular response to lipopolysaccharide
positive regulation of ERK1 and ERK2 cascade
cellular response to peptidoglycan
cellular response to organic cyclic compound
nucleotide-binding oligomerization domain containing signaling pathway
defense response to Gram-positive bacterium
positive regulation of peptidyl-tyrosine phosphorylation
positive regulation of humoral immune response mediated by circulating immunoglobulin
innate immune response
negative regulation of NF-kappaB transcription factor activity
positive regulation of transcription from RNA polymerase II promoter
positive regulation of I-kappaB kinase/NF-kappaB cascade
positive regulation of Notch signaling pathway
JNK cascade
positive regulation of tumor necrosis factor production
positive regulation of epithelial cell proliferation
positive regulation of JNK cascade
innate immune response in mucosa
positive regulation of dendritic cell cytokine production
positive regulation of oxidoreductase activity
positive regulation of monocyte chemotactic protein-1 production
negative regulation of toll-like receptor 2 signaling pathway
positive regulation of stress-activated MAPK cascade
positive regulation of cytokine production involved in inflammatory response
positive regulation of interleukin-1 beta production
positive regulation of interleukin-6 production
positive regulation of NF-kappaB transcription factor activity
positive regulation of MAP kinase activity
negative regulation of interleukin-2 production
negative regulation of macrophage apoptotic process
negative regulation of interleukin-12 production
activation of immune response
intracellular signal transduction
positive regulation of NIK/NF-kappaB signaling
nucleotide-binding oligomerization domain containing 2 signaling pathway
defense response
pattern recognition receptor signaling pathway
activation of MAPK activity
positive regulation of cytokine production involved in immune response
Cellular Component
cell surface
protein-containing complex
plasma membrane
Golgi apparatus
phagocytic vesicle
basolateral plasma membrane
anchored to plasma membrane
Molecular Function
protein kinase binding
actin binding
pattern recognition receptor activity
CARD domain binding
muramyl dipeptide binding
peptidoglycan binding
protein-containing complex binding
ATP binding
enzyme binding
Hsp70 protein binding
Hsp90 protein binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 1040
Molecular Weight 115281.675
Theoretical pI 6.755
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID Q9HC29
UniProtKB/Swiss-Prot Entry Name NOD2_HUMAN
PDB IDs Not Available
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
General References
  1. Tao M, Scacheri PC, Marinis JM, Harhaj EW, Matesic LE, Abbott DW: ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways. Curr Biol. 2009 Aug 11;19(15):1255-63. doi: 10.1016/j.cub.2009.06.038. Epub 2009 Jul 9. [PubMed:19592251 ]
  2. Boada-Romero E, Letek M, Fleischer A, Pallauf K, Ramon-Barros C, Pimentel-Muinos FX: TMEM59 defines a novel ATG16L1-binding motif that promotes local activation of LC3. EMBO J. 2013 Feb 20;32(4):566-82. doi: 10.1038/emboj.2013.8. Epub 2013 Feb 1. [PubMed:23376921 ]
  3. 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. J Biol Chem. 2001 Feb 16;276(7):4812-8. doi: 10.1074/jbc.M008072200. Epub 2000 Nov 21. [PubMed:11087742 ]
  4. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001 May 31;411(6837):599-603. doi: 10.1038/35079107. [PubMed:11385576 ]
  5. Kramer M, Boeck J, Reichenbach D, Kaether C, Schreiber S, Platzer M, Rosenstiel P, Huse K: NOD2-C2 - a novel NOD2 isoform activating NF-kappaB in a muramyl dipeptide-independent manner. BMC Res Notes. 2010 Aug 10;3:224. doi: 10.1186/1756-0500-3-224. [PubMed:20698950 ]
  6. McDonald C, Chen FF, Ollendorff V, Ogura Y, Marchetto S, Lecine P, Borg JP, Nunez G: A role for Erbin in the regulation of Nod2-dependent NF-kappaB signaling. J Biol Chem. 2005 Dec 2;280(48):40301-9. doi: 10.1074/jbc.M508538200. Epub 2005 Oct 3. [PubMed:16203728 ]
  7. Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S, Humke EW, Eckmann L, Powell JJ, Nizet V, Dixit VM, Karin M: A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7803-8. doi: 10.1073/pnas.0802726105. Epub 2008 May 29. [PubMed:18511561 ]
  8. Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, Xiang Y, Bose S: Activation of innate immune antiviral responses by Nod2. Nat Immunol. 2009 Oct;10(10):1073-80. doi: 10.1038/ni.1782. Epub 2009 Aug 23. [PubMed:19701189 ]
  9. Homer CR, Richmond AL, Rebert NA, Achkar JP, McDonald C: ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn's disease pathogenesis. Gastroenterology. 2010 Nov;139(5):1630-41, 1641.e1-2. doi: 10.1053/j.gastro.2010.07.006. Epub 2010 Jul 14. [PubMed:20637199 ]
  10. Zhao Y, Alonso C, Ballester I, Song JH, Chang SY, Guleng B, Arihiro S, Murray PJ, Xavier R, Kobayashi KS, Reinecker HC: Control of NOD2 and Rip2-dependent innate immune activation by GEF-H1. Inflamm Bowel Dis. 2012 Apr;18(4):603-12. doi: 10.1002/ibd.21851. Epub 2011 Sep 1. [PubMed:21887730 ]
  11. Lecat A, Di Valentin E, Somja J, Jourdan S, Fillet M, Kufer TA, Habraken Y, Sadzot C, Louis E, Delvenne P, Piette J, Legrand-Poels S: The c-Jun N-terminal kinase (JNK)-binding protein (JNKBP1) acts as a negative regulator of NOD2 protein signaling by inhibiting its oligomerization process. J Biol Chem. 2012 Aug 24;287(35):29213-26. doi: 10.1074/jbc.M112.355545. Epub 2012 Jun 14. [PubMed:22700971 ]
  12. Lee KH, Biswas A, Liu YJ, Kobayashi KS: Proteasomal degradation of Nod2 protein mediates tolerance to bacterial cell wall components. J Biol Chem. 2012 Nov 16;287(47):39800-11. doi: 10.1074/jbc.M112.410027. Epub 2012 Sep 27. [PubMed:23019338 ]
  13. Menning M, Kufer TA: A role for the Ankyrin repeat containing protein Ankrd17 in Nod1- and Nod2-mediated inflammatory responses. FEBS Lett. 2013 Jul 11;587(14):2137-42. doi: 10.1016/j.febslet.2013.05.037. Epub 2013 May 24. [PubMed:23711367 ]
  14. Fiil BK, Damgaard RB, Wagner SA, Keusekotten K, Fritsch M, Bekker-Jensen S, Mailand N, Choudhary C, Komander D, Gyrd-Hansen M: OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. Mol Cell. 2013 Jun 27;50(6):818-830. doi: 10.1016/j.molcel.2013.06.004. [PubMed:23806334 ]
  15. Parkhouse R, Boyle JP, Mayle S, Sawmynaden K, Rittinger K, Monie TP: Interaction between NOD2 and CARD9 involves the NOD2 NACHT and the linker region between the NOD2 CARDs and NACHT domain. FEBS Lett. 2014 Aug 25;588(17):2830-6. doi: 10.1016/j.febslet.2014.06.035. Epub 2014 Jun 21. [PubMed:24960071 ]
  16. Parkhouse R, Boyle JP, Monie TP: Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators. FEBS Lett. 2014 Sep 17;588(18):3382-9. doi: 10.1016/j.febslet.2014.07.029. Epub 2014 Aug 2. [PubMed:25093298 ]
  17. Thiebaut R, Esmiol S, Lecine P, Mahfouz B, Hermant A, Nicoletti C, Parnis S, Perroy J, Borg JP, Pascoe L, Hugot JP, Ollendorff V: Characterization and Genetic Analyses of New Genes Coding for NOD2 Interacting Proteins. PLoS One. 2016 Nov 3;11(11):e0165420. doi: 10.1371/journal.pone.0165420. eCollection 2016. [PubMed:27812135 ]
  18. Yan J, Hedl M, Abraham C: An inflammatory bowel disease-risk variant in INAVA decreases pattern recognition receptor-induced outcomes. J Clin Invest. 2017 Jun 1;127(6):2192-2205. doi: 10.1172/JCI86282. Epub 2017 Apr 24. [PubMed:28436939 ]
  19. Normand S, Waldschmitt N, Neerincx A, Martinez-Torres RJ, Chauvin C, Couturier-Maillard A, Boulard O, Cobret L, Awad F, Huot L, Ribeiro-Ribeiro A, Lautz K, Ruez R, Delacre M, Bondu C, Guilliams M, Scott C, Segal A, Amselem S, Hot D, Karabina S, Bohn E, Ryffel B, Poulin LF, Kufer TA, Chamaillard M: Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens. Nat Commun. 2018 Dec 17;9(1):5338. doi: 10.1038/s41467-018-07750-5. [PubMed:30559449 ]
  20. Tukel T, Shalata A, Present D, Rachmilewitz D, Mayer L, Grant D, Risch N, Desnick RJ: Crohn disease: frequency and nature of CARD15 mutations in Ashkenazi and Sephardi/Oriental Jewish families. Am J Hum Genet. 2004 Apr;74(4):623-36. doi: 10.1086/382226. Epub 2004 Mar 5. [PubMed:15024686 ]
  21. Kanazawa N, Okafuji I, Kambe N, Nishikomori R, Nakata-Hizume M, Nagai S, Fuji A, Yuasa T, Manki A, Sakurai Y, Nakajima M, Kobayashi H, Fujiwara I, Tsutsumi H, Utani A, Nishigori C, Heike T, Nakahata T, Miyachi Y: Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. Blood. 2005 Feb 1;105(3):1195-7. doi: 10.1182/blood-2004-07-2972. Epub 2004 Sep 30. [PubMed:15459013 ]
  22. van Duist MM, Albrecht M, Podswiadek M, Giachino D, Lengauer T, Punzi L, De Marchi M: A new CARD15 mutation in Blau syndrome. Eur J Hum Genet. 2005 Jun;13(6):742-7. doi: 10.1038/sj.ejhg.5201404. [PubMed:15812565 ]
  23. Schnitzler F, Brand S, Staudinger T, Pfennig S, Hofbauer K, Seiderer J, Tillack C, Goke B, Ochsenkuhn T, Lohse P: Eight novel CARD15 variants detected by DNA sequence analysis of the CARD15 gene in 111 patients with inflammatory bowel disease. Immunogenetics. 2006 Apr;58(2-3):99-106. doi: 10.1007/s00251-005-0073-2. Epub 2006 Feb 17. [PubMed:16485124 ]
  24. Okafuji I, Nishikomori R, Kanazawa N, Kambe N, Fujisawa A, Yamazaki S, Saito M, Yoshioka T, Kawai T, Sakai H, Tanizaki H, Heike T, Miyachi Y, Nakahata T: Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis. Arthritis Rheum. 2009 Jan;60(1):242-50. doi: 10.1002/art.24134. [PubMed:19116920 ]
  25. Okada S, Konishi N, Tsumura M, Shirao K, Yasunaga S, Sakai H, Nishikomori R, Takihara Y, Kobayashi M: Cardiac infiltration in early-onset sarcoidosis associated with a novel heterozygous mutation, G481D, in CARD15. Rheumatology (Oxford). 2009 Jun;48(6):706-7. doi: 10.1093/rheumatology/kep061. Epub 2009 Apr 9. [PubMed:19359344 ]
  26. Milman N, Ursin K, Rodevand E, Nielsen FC, Hansen TV: A novel mutation in the NOD2 gene associated with Blau syndrome: a Norwegian family with four affected members. Scand J Rheumatol. 2009 May-Jun;38(3):190-7. doi: 10.1080/03009740802464194. [PubMed:19169908 ]
  27. Stoevesandt J, Morbach H, Martin TM, Zierhut M, Girschick H, Hamm H: Sporadic Blau syndrome with onset of widespread granulomatous dermatitis in the newborn period. Pediatr Dermatol. 2010 Jan-Feb;27(1):69-73. doi: 10.1111/j.1525-1470.2009.01060.x. [PubMed:20199415 ]
  28. Yao Q, Zhou L, Cusumano P, Bose N, Piliang M, Jayakar B, Su LC, Shen B: A new category of autoinflammatory disease associated with NOD2 gene mutations. Arthritis Res Ther. 2011;13(5):R148. doi: 10.1186/ar3462. Epub 2011 Sep 14. [PubMed:21914217 ]
  29. Zeybek C, Basbozkurt G, Gul D, Demirkaya E, Gok F: A new mutation in blau syndrome. Case Rep Rheumatol. 2015;2015:463959. doi: 10.1155/2015/463959. Epub 2015 Jan 27. [PubMed:25692065 ]
  30. de Inocencio J, Mensa-Vilaro A, Tejada-Palacios P, Enriquez-Merayo E, Gonzalez-Roca E, Magri G, Ruiz-Ortiz E, Cerutti A, Yague J, Arostegui JI: Somatic NOD2 mosaicism in Blau syndrome. J Allergy Clin Immunol. 2015 Aug;136(2):484-7.e2. doi: 10.1016/j.jaci.2014.12.1941. Epub 2015 Feb 25. [PubMed:25724124 ]
  31. Yao Q, Shen M, McDonald C, Lacbawan F, Moran R, Shen B: NOD2-associated autoinflammatory disease: a large cohort study. Rheumatology (Oxford). 2015 Oct;54(10):1904-12. doi: 10.1093/rheumatology/kev207. Epub 2015 Jun 11. [PubMed:26070941 ]