NOD2

Official Full Name

nucleotide binding oligomerization domain containing 2

Organism

Homo sapiens

GeneID

64127

Background

This gene is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing the muramyl dipeptide (MDP) derived from them and activating the NFKB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

Synonyms

CD; ACUG; BLAU; IBD1; YAOS; BLAUS; NLRC2; NOD2B; CARD15; CLR16.3; PSORAS1;

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Detailed Information

Nucleotide-binding oligomerization domain 2 (NOD2) belongs to the NOD-like receptor family. As an intracellular pattern recognition receptor, NOD2 participates in host cell recognition of pathogens by recognizing the ligand muramyl dipeptide, which mediates immune inflammatory response. Recent studies have found that NOD2 plays an important role in the occurrence and development of various cardiovascular diseases such as myocarditis, atherosclerosis, and myocardial infarction.

NOD2-mediated Signal Transduction

NOD2 also triggers multiple signaling pathways in response to pathogenic microorganisms in the cytoplasm. Studies have shown that respiratory syncytial virus (RSV) infection causes NOD2 to transfer to mitochondria, where it binds to mitochondrial antiviral signaling protein (MAV), activates IRF3 in turn, and then produces IFN-β. Therefore, it is possible that NOD2 binding to peptidoglycan induces the recruitment and activation of RIPK2, and it may also bind to ssRNA, which causes NOD2 to transfer to mitochondria and activate MAV-dependent signaling pathways.

Nod2 Figure 1. Mechanisms by which muramyl dipeptide (MDP)enters into cells to trigger Nod2 signaling. (Nabhani, Z. A. , et al. 2017)

NOD2 can recognize the lytic product MDP of bacterial cell wall peptidoglycans, and is widely involved in the identification and inflammatory response of intracellular pathogenic microorganisms, but studies have shown that NOD2 can also identify virus components. NOD2 can generate an immune response to single-stranded RNA and can activate IRF3 to produce IFN-β. Infection with respiratory syncytial virus, cytoplasmic stomatitis, or influenza virus can be observed with NOD2-mediated IRF3 activation. Studies have found that NOD2 can recognize human macrophage virus (HCMV) in the herpesviridae family. This virus contains both DNA and RNA. After HCMV infection of U373 glioma cells, the expression of NOD2 increased significantly, downstream inflammatory factors such as IFN-β, IL-8 expression increased, and virus replication was inhibited. However, the same test with herpes virus 1 and herpes virus 2 did not activate NOD2. NOD2 is closely related to mucosal immunity. A large number of studies have shown that the development and development of Crohn's disease, a human intestinal disease, is closely related to the sudden change of NOD2. Studies have found that NOD2 can prevent inflammation of the small intestine by limiting the spread of common Bacteroides.

NOD2 and Disease

Studies have shown that NOD2 functions as a virus pattern recognition receptor-inducing the production of type 1 interferons in the response of the RNA virus, which plays a crucial role. Studies in primary endothelial cells isolated from female reproductive tracts have shown that NOD2 is up-regulated during stimuli such as HIV-1. Therefore, NOD2 may be involved in the regulation of HIV infection. The most common cause of viral myocarditis is coxsackie virus infection. It was found that in cardiac myositis caused by coxsackie virus B3 (CVB3), NOD2 expression increases. Knockout of the mouse NOD2 receptor can improve myocardial inflammation and reduce cardiac function damage. Mesenchymal stem cells (MSC) can improve the symptoms of CVB3-induced myocarditis by inhibiting the expression of NOD2 and reducing the release of inflammatory mediators. These studies suggest that NOD2 plays an important role in viral myocarditis.

The descending aorta was ligated to NOD2 knockout mice and it was found that the worsening of cardiac function was significantly worse than that of wild type mice. In addition, cardiac mass/body mass ratio, cardiac mass/tibia length ratio, and myocardial hypertrophy-related indicators such as myocardial cell cross-sectional area increased significantly, indirectly proving that NOD2 can inhibit myocardial hypertrophy and myocardial fibrosis. Further, the expression of NOD2 and Toll-like receptor 4 (TLR4) in myocardial tissue of wild-type mice increased after ligation of the descending aorta, and the expression of TLR4 in NOD2 gene knockout mice increased even more. Studies have found that after suppressing NOD2 in macrophages with siRNA, macrophages were stimulated with lipopolysaccharide (LPS), a TLR4 receptor agonist, and the inflammatory response in mice was significantly enhanced.

References:

Nabhani, Z. A. , Dietrich, G. , Hugot, J. P. , & Barreau, F. . (2017). Nod2: the intestinal gate keeper. PLoS Pathogens, 13(3), e1006177.
Anna, N. , Maria, P. , Salvatore, C. , & Laura, S. . (2018). Nod2 and inflammation: current insights. Journal of Inflammation Research, Volume 11, 49-60.
Keestra-Gounder, A. Marijke, & Tsolis, Renée M. . Nod1 and nod2: beyond peptidoglycan sensing. Trends in Immunology, S1471490617301424.

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