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Gene Review

NOD1  -  nucleotide-binding oligomerization domain...

Homo sapiens

Synonyms: CARD4, CLR7.1, Caspase recruitment domain-containing protein 4, NLRC1, Nucleotide-binding oligomerization domain-containing protein 1
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Disease relevance of NOD1


High impact information on NOD1


Chemical compound and disease context of NOD1


Biological context of NOD1

  • NOD1 (CARD4) is located on chromosome 7p14.3, in a region of known linkage to IBD and encodes an intracellular bacterial pathogen-associated molecular pattern receptor that is closely related to NOD2 [2].
  • Instead, our findings demonstrate that this response is mediated by a cytosolic, plant disease resistance-like protein called CARD4/Nod1 [13].
  • PATIENTS AND METHODS: The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients [14].
  • Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence [14].
  • CONCLUSION: Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD [14].

Anatomical context of NOD1

  • In this context, CARD4/NOD1 is a candidate for a recognition protein of intracellular bacteria or peptidoglycan in intestinal epithelial cells [15].
  • These findings in two independent populations provide strong evidence for a role for NOD1 variants in IBD susceptibility and reinforce the role of the innate immune system in IBD pathogenesis [2].
  • NOD1/NOD2 expression levels were induced in the gastric epithelium in H. pylori-positive patients [3].
  • The aim of these studies was to assess the functional importance of Nod1 in activating NF-kappaB and NF-kappaB proinflammatory target genes in human intestinal epithelium [16].
  • Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells [17].

Associations of NOD1 with chemical compounds

  • Dominant-negative versions of CARD4 block activation of NF-kappaB and JNK by S. flexneri as well as microinjected LPS [13].
  • Nod1, a protein with an NH2-terminal CARD-linked to a nucleotide-binding domain and a COOH-terminal segment with multiple leucine-rich repeats, was identified [18].
  • Conversely, overexpression of Nod1 in MCF-7 cells results in inhibition of estrogen-dependent tumor growth and reduction of estrogen-induced proliferative responses in vitro [4].
  • NOD1 is an intracellular PRR that initiates inflammation in response to bacterial diaminopimelic acid (iE-DAP) [19].
  • Whereas Nod2 detects GlcNAc-MurNAc dipeptide (GM-Di), Nod1 senses a unique diaminopimelate-containing GlcNAc-MurNAc tripeptide muropeptide (GM-TriDAP) found mostly in Gram-negative bacterial PGs [20].

Physical interactions of NOD1

  • Cross-talk between cytosolic NOD1 and membrane-bound TLR enhances responses to the multiple antigens simultaneously presented by a microbe [21].

Regulatory relationships of NOD1

  • Normal responses to specific NOD1-activating peptidoglycan agonists in the presence of the NOD2 frameshift and other mutations in Crohn's disease [22].
  • Here we show that bacterial lipopolysaccharides, but not other pathogen components tested, induced TLR4- and MyD88-independent NF-kappaB activation in human embryonic kidney 293T cells expressing trace amounts of Nod1 [23].
  • We conclude that signaling through Nod1 is required for activating NF-kappaB in human intestinal epithelial cells infected with gram-negative enteric bacteria that can bypass TLR activation [16].
  • NOD2/CARD15 variant carriage had no influence on NOD1/CARD4 effect on IBD susceptibility [24].

Other interactions of NOD1

  • Cardiak and Nod1 (but not other CARD proteins) also exhibited opposing effects on CARD6 protein phosphorylation and expression, providing further evidence of functional interactions among these proteins in cells [25].
  • These studies suggest that the Th1 cytokine, IFN gamma, activates CARD4/NOD1 transcription and regulate innate immune mechanisms in the condition of intestinal mucosal inflammation [15].
  • Interferon-gamma augments CARD4/NOD1 gene and protein expression through interferon regulatory factor-1 in intestinal epithelial cells [15].
  • Finally, we showed that invasive S. flexneri triggers the formation of a transient complex involving CARD4, RICK and the IKK complex [13].
  • Nod1 is a member of a growing family of intracellular proteins with structural homology to apoptosis regulators Apaf-1/Ced-4 and a class of plant disease-resistant gene products [23].

Analytical, diagnostic and therapeutic context of NOD1


  1. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells. Rosenstiel, P., Fantini, M., Bräutigam, K., Kühbacher, T., Waetzig, G.H., Seegert, D., Schreiber, S. Gastroenterology (2003) [Pubmed]
  2. Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. McGovern, D.P., Hysi, P., Ahmad, T., van Heel, D.A., Moffatt, M.F., Carey, A., Cookson, W.O., Jewell, D.P. Hum. Mol. Genet. (2005) [Pubmed]
  3. Influence of polymorphisms in the NOD1/CARD4 and NOD2/CARD15 genes on the clinical outcome of Helicobacter pylori infection. Rosenstiel, P., Hellmig, S., Hampe, J., Ott, S., Till, A., Fischbach, W., Sahly, H., Lucius, R., Fölsch, U.R., Philpott, D., Schreiber, S. Cell. Microbiol. (2006) [Pubmed]
  4. Nod1-dependent control of tumor growth. da Silva Correia, J., Miranda, Y., Austin-Brown, N., Hsu, J., Mathison, J., Xiang, R., Zhou, H., Li, Q., Han, J., Ulevitch, R.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  5. Identification of the critical residues involved in peptidoglycan detection by Nod1. Girardin, S.E., Jéhanno, M., Mengin-Lecreulx, D., Sansonetti, P.J., Alzari, P.M., Philpott, D.J. J. Biol. Chem. (2005) [Pubmed]
  6. pH-dependent internalization of muramyl peptides from early endosomes enables Nod1 and Nod2 signaling. Lee, J., Tattoli, I., Wojtal, K.A., Vavricka, S.R., Philpott, D.J., Girardin, S.E. J. Biol. Chem. (2009) [Pubmed]
  7. Detection of peptidoglycans by NOD proteins. Royet, J., Reichhart, J.M. Trends Cell Biol. (2003) [Pubmed]
  8. Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo. Masumoto, J., Yang, K., Varambally, S., Hasegawa, M., Tomlins, S.A., Qiu, S., Fujimoto, Y., Kawasaki, A., Foster, S.J., Horie, Y., Mak, T.W., Núñez, G., Chinnaiyan, A.M., Fukase, K., Inohara, N. J. Exp. Med. (2006) [Pubmed]
  9. NOD proteins: an intracellular pathogen-recognition system or signal transduction modifiers? Murray, P.J. Curr. Opin. Immunol. (2005) [Pubmed]
  10. Intestinal myofibroblasts in innate immune responses of the intestine. Otte, J.M., Rosenberg, I.M., Podolsky, D.K. Gastroenterology (2003) [Pubmed]
  11. A critical role for peptidoglycan N-deacetylation in Listeria evasion from the host innate immune system. Boneca, I.G., Dussurget, O., Cabanes, D., Nahori, M.A., Sousa, S., Lecuit, M., Psylinakis, E., Bouriotis, V., Hugot, J.P., Giovannini, M., Coyle, A., Bertin, J., Namane, A., Rousselle, J.C., Cayet, N., Prévost, M.C., Balloy, V., Chignard, M., Philpott, D.J., Cossart, P., Girardin, S.E. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  12. Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients. Adib-Conquy, M., Adrie, C., Fitting, C., Gattolliat, O., Beyaert, R., Cavaillon, J.M. Crit. Care Med. (2006) [Pubmed]
  13. CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. Girardin, S.E., Tournebize, R., Mavris, M., Page, A.L., Li, X., Stark, G.R., Bertin, J., DiStefano, P.S., Yaniv, M., Sansonetti, P.J., Philpott, D.J. EMBO Rep. (2001) [Pubmed]
  14. CARD4/NOD1 is not involved in inflammatory bowel disease. Zouali, H., Lesage, S., Merlin, F., Cézard, J.P., Colombel, J.F., Belaiche, J., Almer, S., Tysk, C., O'Morain, C., Gassull, M., Christensen, S., Finkel, Y., Modigliani, R., Gower-Rousseau, C., Macry, J., Chamaillard, M., Thomas, G., Hugot, J.P. Gut (2003) [Pubmed]
  15. Interferon-gamma augments CARD4/NOD1 gene and protein expression through interferon regulatory factor-1 in intestinal epithelial cells. Hisamatsu, T., Suzuki, M., Podolsky, D.K. J. Biol. Chem. (2003) [Pubmed]
  16. Nod1 is an essential signal transducer in intestinal epithelial cells infected with bacteria that avoid recognition by toll-like receptors. Kim, J.G., Lee, S.J., Kagnoff, M.F. Infect. Immun. (2004) [Pubmed]
  17. Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells. Tada, H., Aiba, S., Shibata, K., Ohteki, T., Takada, H. Infect. Immun. (2005) [Pubmed]
  18. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. Inohara, N., Koseki, T., del Peso, L., Hu, Y., Yee, C., Chen, S., Carrio, R., Merino, J., Liu, D., Ni, J., Núñez, G. J. Biol. Chem. (1999) [Pubmed]
  19. NOD1 variation, immunoglobulin E and asthma. Hysi, P., Kabesch, M., Moffatt, M.F., Schedel, M., Carr, D., Zhang, Y., Boardman, B., von Mutius, E., Weiland, S.K., Leupold, W., Fritzsch, C., Klopp, N., Musk, A.W., James, A., Nunez, G., Inohara, N., Cookson, W.O. Hum. Mol. Genet. (2005) [Pubmed]
  20. Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2. Girardin, S.E., Travassos, L.H., Hervé, M., Blanot, D., Boneca, I.G., Philpott, D.J., Sansonetti, P.J., Mengin-Lecreulx, D. J. Biol. Chem. (2003) [Pubmed]
  21. Synergistic enhancement of Toll-like receptor responses by NOD1 activation. van Heel, D.A., Ghosh, S., Butler, M., Hunt, K., Foxwell, B.M., Mengin-Lecreulx, D., Playford, R.J. Eur. J. Immunol. (2005) [Pubmed]
  22. Normal responses to specific NOD1-activating peptidoglycan agonists in the presence of the NOD2 frameshift and other mutations in Crohn's disease. van Heel, D.A., Hunt, K.A., Ghosh, S., Hervé, M., Playford, R.J. Eur. J. Immunol. (2006) [Pubmed]
  23. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. Inohara, N., Ogura, Y., Chen, F.F., Muto, A., Nuñez, G. J. Biol. Chem. (2001) [Pubmed]
  24. Investigation of NOD1/CARD4 variation in inflammatory bowel disease using a haplotype-tagging strategy. Van Limbergen, J., Nimmo, E.R., Russell, R.K., Drummond, H.E., Smith, L., Anderson, N.H., Davies, G., Arnott, I.D., Wilson, D.C., Satsangi, J. Hum. Mol. Genet. (2007) [Pubmed]
  25. CARD6 is a modulator of NF-kappa B activation by Nod1- and Cardiak-mediated pathways. Stehlik, C., Hayashi, H., Pio, F., Godzik, A., Reed, J.C. J. Biol. Chem. (2003) [Pubmed]
  26. Differential Release and Distribution of Nod1 and Nod2 Immunostimulatory Molecules among Bacterial Species and Environments. Hasegawa, M., Yang, K., Hashimoto, M., Park, J.H., Kim, Y.G., Fujimoto, Y., Nuñez, G., Fukase, K., Inohara, N. J. Biol. Chem. (2006) [Pubmed]
  27. Purification, crystallization and preliminary crystallographic characterization of the caspase-recruitment domain of human Nod1. Srimathi, T., Robbins, S.L., Dubas, R.L., Seo, J.H., Park, Y.C. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. (2007) [Pubmed]
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