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NOD2

Identifiers

NOD2, ACUG, BLAU, CARD15, CD, CLR16.3, IBD1, NLRC2, NOD2B, PSORAS1, nucleotide binding oligomerization domain containing 2, BLAUS, YAOS

External IDs

OMIM: 605956; MGI: 2429397; GeneCards: NOD2

Available structures

PDB

Ortholog search: PDBe RCSB

List of PDB id codes
5IRL, 5IRM, 5IRN

Gene location (Human)

Chr.	Chromosome 16 (human)^[1]

Band	16q12.1	Start	50,693,588 bp^[1]
Band	16q12.1	End	50,734,041 bp^[1]

Gene location (Mouse)

Chr.	Chromosome 8 (mouse)^[2]

Band	8\|8 C3	Start	89,373,943 bp^[2]
Band	8\|8 C3	End	89,415,102 bp^[2]

RNA expression pattern

Bgee

Human

Mouse (ortholog)

Top expressed in

monocyte

granulocyte

blood

skin of leg

skin of abdomen

vulva

human penis

cartilage tissue

bone marrow cell

vagina

Top expressed in

granulocyte

secondary oocyte

primary oocyte

zygote

embryo

esophagus

zone of skin

quadriceps femoris muscle

duodenum

More reference expression data

BioGPS


More reference expression data

Gene ontology
Molecular function	Hsp90 protein binding nucleotide binding Hsp70 protein binding protein binding peptidoglycan binding enzyme binding actin binding CARD domain binding ATP binding protein kinase binding muramyl dipeptide binding protein-containing complex binding
Cellular component	cytoplasm cytosol vesicle membrane plasma membrane cell surface basolateral plasma membrane COP9 signalosome cytoskeleton Golgi apparatus mitochondrion protein-containing complex
Biological process	positive regulation of prostaglandin-endoperoxide synthase activity regulation of apoptotic process defense response detection of biotic stimulus cytokine production involved in immune response positive regulation of cytokine production involved in inflammatory response intracellular signal transduction detection of muramyl dipeptide positive regulation of interleukin-10 production positive regulation of epithelial cell proliferation immune system process positive regulation of oxidoreductase activity response to muramyl dipeptide positive regulation of prostaglandin-E synthase activity positive regulation of JNK cascade positive regulation of nitric-oxide synthase biosynthetic process positive regulation of NIK/NF-kappaB signaling positive regulation of phosphatidylinositol 3-kinase activity positive regulation of gamma-delta T cell activation cellular response to muramyl dipeptide JNK cascade negative regulation of macrophage apoptotic process positive regulation of dendritic cell antigen processing and presentation nucleotide-binding oligomerization domain containing 2 signaling pathway maintenance of gastrointestinal epithelium defense response to bacterium positive regulation of NF-kappaB transcription factor activity positive regulation of interleukin-8 production detection of bacterium positive regulation of interleukin-1 beta production regulation of inflammatory response positive regulation of interleukin-6 production protein complex oligomerization positive regulation of tumor necrosis factor production positive regulation of ERK1 and ERK2 cascade positive regulation of I-kappaB kinase/NF-kappaB signaling positive regulation of B cell activation positive regulation of interleukin-17 production positive regulation of type 2 immune response nucleotide-binding oligomerization domain containing signaling pathway positive regulation of stress-activated MAPK cascade positive regulation of Notch signaling pathway positive regulation of transcription by RNA polymerase II cellular response to organic cyclic compound positive regulation of cell population proliferation innate immune response response to nutrient positive regulation of dendritic cell cytokine production positive regulation of protein K63-linked ubiquitination cellular response to peptidoglycan positive regulation of MAP kinase activity interleukin-1-mediated signaling pathway cellular response to lipopolysaccharide
Sources:Amigo / QuickGO

Orthologs

Databases

NCBI: entry; OMA: entry

Species

Human

Mouse

Entrez


64127


257632

Ensembl


ENSG00000167207


ENSMUSG00000055994

UniProt


Q9HC29


Q80SY9

RefSeq (mRNA)


NM_001293557 NM_022162 NM_001370466


NM_145857

RefSeq (protein)


NP_001280486 NP_071445 NP_001357395


NP_665856

Location (UCSC)

Chr 16: 50.69 – 50.73 Mb

Chr 8: 89.37 – 89.42 Mb

PubMed search

^[3]

^[4]

Wikidata

View/Edit Human

View/Edit Mouse

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.^[5]^[6] NOD2 plays an important role in the immune system. It recognizes bacterial molecules (peptidoglycans) and stimulates an immune reaction.^[7]

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.^[8]

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^[9]

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.^[10]

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.^[11]

Clinical significance

Mutations in this gene have been associated with serious autoimmune diseases like Crohn's disease,^[9] Blau syndrome, pulmonary sarcoidosis^[12] and Graft-versus-host disease.^[13]^[14]^[15]

Loss of function mutations of NOD2 have been associated with better response to cancer therapy with PD-1/PD-L1 immune checkpoint blockade.^[16]

Interactions

NOD2 has been shown to interact with NLRC4.^[17]^[18]

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.^[19]

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000167207 – Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000055994 – Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ Gilberts EC, Greenstein AJ, Katsel P, Harpaz N, Greenstein RJ (December 1994). "Molecular evidence for two forms of Crohn disease". Proceedings of the National Academy of Sciences of the United States of America. 91 (26): 12721–12724. Bibcode:1994PNAS...9112721G. 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): 821–823. Bibcode:1996Natur.379..821H. doi:10.1038/379821a0. PMID 8587604. S2CID 4311407.
↑ Mahla RS, Reddy MC, Prasad DV, Kumar H (September 2013). "Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology". Frontiers in Immunology. 4: 248. doi:10.3389/fimmu.2013.00248. PMC 3759294. PMID 24032031.
↑ Kufer TA, Banks DJ, Philpott DJ (August 2006). "Innate immune sensing of microbes by Nod proteins". Annals of the New York Academy of Sciences. 1072 (1): 19–27. Bibcode:2006NYASA1072...19K. doi:10.1196/annals.1326.020. PMID 17057187. S2CID 20217610.
1 2 Nakagome S, Mano S, Kozlowski L, Bujnicki JM, Shibata H, Fukumaki Y, et al. (June 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): 1569–1585. doi:10.1093/molbev/mss006. PMC 3697811. PMID 22319155.
↑ 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". The Journal of Biological Chemistry. 276 (7): 4812–4818. doi:10.1074/jbc.M008072200. PMID 11087742.
↑ "Entrez Gene: NOD2 nucleotide-binding oligomerization domain containing 2".
↑ Sato H, Williams HR, Spagnolo P, Abdallah A, Ahmad T, Orchard TR, et al. (February 2010). "CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis". The European Respiratory Journal. 35 (2): 324–330. doi:10.1183/09031936.00010209. hdl:11380/983383. PMID 19679608.
↑ Zhao H, Jia M, Wang Z, Cheng Y, Luo Z, Chen Y, et al. (June 2015). "Association between NOD2 single nucleotide polymorphisms and Grade III-IV acute graft-versus-host disease: A meta-analysis". Hematology. 20 (5): 254–262. doi:10.1179/1607845414Y.0000000202. PMID 25248089. S2CID 206850232.
↑ Radford-Smith G, Pandeya N (November 2006). "Associations between NOD2/CARD15 genotype and phenotype in Crohn's disease--Are we there yet?". World Journal of Gastroenterology. 12 (44): 7097–7103. doi:10.3748/wjg.v12.i44.7097. PMC 4087769. 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". Rheumatology International. 27 (3): 257–262. doi:10.1007/s00296-006-0250-0. PMID 17096091. S2CID 23739992.
↑ Barnet MB, Jackson KJ, Masle-Farquhar E, Russell A, Burnett DL, Chye A, et al. (July 2025). "Common inherited loss-of-function mutations in the innate sensor NOD2 contribute to exceptional immune response to cancer immunotherapy". Proceedings of the National Academy of Sciences of the United States of America. 122 (28) e2314258122. doi:10.1073/pnas.2314258122. PMC 12280981. PMID 40623177.
↑ Damiano JS, Oliveira V, Welsh K, Reed JC (July 2004). "Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses". The Biochemical Journal. 381 (Pt 1): 213–219. 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. (October 2009). "Activation of innate immune antiviral responses by Nod2". Nature Immunology. 10 (10): 1073–1080. doi:10.1038/ni.1782. PMC 2752345. PMID 19701189.