Alternative titles; symbols
HGNC Approved Gene Symbol: NOD1
Cytogenetic location: 7p14.3 Genomic coordinates (GRCh38) : 7:30,424,527-30,478,784 (from NCBI)
Inflammatory responses are triggered when pattern-recognition receptors (PRRs) detect tissue damage or microbial infection. NOD1 belongs to the nucleotide-binding oligomerization domain (NOD)-like receptor family of PRRs (summary by Keestra-Gounder et al., 2016).
APAF1 (602233) in mammals and Ced4 in the worm are members of a family of intracellular proteins composed of an N-terminal caspase recruitment domain (CARD), a centrally located nucleotide-binding domain (NBD), and a C-terminal regulatory domain, which consists of WD40 repeats in the case of APAF1. The APAF1 WD40 repeats act as recognition domains for mitochondrial damage, which leads to APAF1 oligomerization and eventual apoptosis through homophilic CARD-CARD interaction with the prodomain of caspase-9 (CASP9; 602234). By searching a proprietary EST database for sequences encoding CARD motifs, followed by screening an endothelial cell cDNA library, Bertin et al. (1999) obtained a cDNA encoding CARD4. The deduced 953-amino acid CARD4 protein contains an N-terminal CARD motif, an NBD, and unlike APAF1, 10 tandem leucine-rich repeats (LRRs) in its C terminus. Northern blot analysis revealed abundant expression of a 4.5-kb transcript in adult heart, spleen, and lung, as well as in numerous cancer cell lines and fetal tissues.
Using similar methods, Inohara et al. (1999) cloned and characterized CARD4, which they called NOD1. Northern blot analysis detected wide expression of NOD1. In situ hybridization analysis showed relatively restricted expression of Nod1 in day-15.5 mouse embryos. Confocal microscopy demonstrated that NOD1 is a cytosolic protein.
By genomic sequence analysis, Inohara et al. (1999) determined that the NOD1 gene contains 7 coding and 7 noncoding exons.
By genomic sequence analysis, Inohara et al. (1999) determined that the NOD1 gene maps to 7p15-p14.
By yeast 2-hybrid analysis using the CARD domain of CARD4 as bait to screen breast, prostate, and brain cDNA libraries, as well as coimmunoprecipitation analysis, Bertin et al. (1999) found preferential interaction with the CARD of RICK (RIPK2; 603455). Luciferase reporter analysis showed that the CARD domain of CARD4, but not that of APAF1, potently induces activation of nuclear factor kappa-B (see 164011), but not of JUN N-terminal kinase (see 601158), in a concentration-dependent manner.
Coimmunoprecipitation analysis by Inohara et al. (1999) revealed that NOD1 preferentially interacts with procaspases containing CARDs or death effector domains (DEDs), as well as with itself, RICK, and CLARP (CFLAR; 603599), but not with RAIDD (CRADD; 603454), APAF1, NIK (604655), or other CARD- or DED-containing proteins. Functional analysis indicated that the CARD and NBD of NOD1, but not the LRR, enhance apoptosis induced by CASP9, but not by other caspases or CLARP. The CARD was found to be essential for NOD1 to bind and activate CASP9, as well as to promote apoptosis. Inohara et al. (1999) also observed that NOD1 interacts with RICK in NFKB activation.
Chamaillard et al. (2003) noted that NOD2/CARD15 (605956) recognizes muramyldipeptide (MDP), which is conserved in the cell wall peptidoglycan (PGN) of practically all bacteria, and that NOD1 mediates responsiveness to various gram-negative bacteria through its C-terminal LRRs. Using biochemical and genetic approaches, they demonstrated that PGN containing gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP) is uniquely present in gram-negative bacilli and particular gram-positive bacteria and is recognized by the NOD1-mediated pathway. Murine macrophages deficient in Nod1 failed to secrete cytokines in response to synthetic iE-DAP and did not prime the lipopolysaccharide response. Chamaillard et al. (2003) concluded that NOD1 acts as an intracellular pattern recognition receptor for a subset of bacteria through the detection of iE-DAP. They proposed that, given the nonoverlapping PGN-derived structures recognized by NOD1 and NOD2, it may be possible to restore deficient NOD2 function in patients with Crohn disease (266600) through stimulation of NOD1 signaling at intestinal sites with ie-DAP analogs.
Girardin et al. (2003) demonstrated that human NOD1 specifically detects a unique diaminopimelate-containing N-acetylglucosamine-N-acetylmuramic acid (GlcNAc-MurNAc) tripeptide motif found in gram-negative bacterial peptidoglycan, resulting in activation of the transcription factor NF-kappa-B pathway. Moreover, they showed that in epithelial cells, NOD1 is indispensable for intracellular gram-negative bacterial sensing.
Using NOD1-deficient and intact human breast cancer cell lines, da Silva Correia et al. (2006) found that susceptibility to apoptosis required NOD1. Severe combined immunodeficiency (SCID) mice bearing implanted estrogen pellets grew larger tumors when injected with NOD1-deficient cells than when injected with the parental cell line. NOD1-deficient cells in which NOD1 was reintroduced did not produce tumors when injected in SCID mice. Da Silva Correia et al. (2006) proposed that the innate immune system regulates tumor growth in part through the NOD1 pathway.
Intestinal lymphoid tissues generate flora-reactive IgA-producing B cells, and include Peyer patches and mesenteric lymph nodes as well as numerous isolated lymphoid follicles (ILFs). Bouskra et al. (2008) showed that peptidoglycan from gram-negative bacteria is necessary and sufficient to induce the genesis of ILFs in mice through recognition by the NOD1 innate receptor in epithelial cells, and beta-defensin-3 (606611)- and CCL20 (601960)-mediated signaling through the chemokine receptor CCR6 (601835). Maturation of ILFs into large B-cell clusters requires subsequent detection of bacteria by Toll-like receptors. In the absence of ILFs, the composition of the intestinal bacterial community is profoundly altered. Bouskra et al. (2008) concluded that intestinal bacterial commensals and the immune system communicate through an innate detection system to generate adaptive lymphoid tissues and maintain intestinal homeostasis.
Yeretssian et al. (2011) used genomewide RNA interference to identify candidate genes that modulate the NOD1 inflammatory response in intestinal epithelial cells. Their results revealed a significant crosstalk between innate immunity and apoptosis and identified BID (601997) as a critical component of the inflammatory response. Colonocytes depleted of BID or macrophages from Bid-null mice are markedly defective in cytokine production in response to NOD activation. Furthermore, Bid-null mice are unresponsive to local or systemic exposure to NOD agonists or their protective effect in experimental colitis. Mechanistically, BID interacts with NOD1, NOD2, and the I-kappa-B kinase complex (see 600664), impacting NF-kappa-B and extracellular signal-regulated kinase (ERK; see 601795) signaling. Yeretssian et al. (2011) concluded that their results defined a novel role of BID in inflammation and immunity independent of its apoptotic function, furthering the evidence of evolutionary conservation between the mechanisms of apoptosis and immunity.
Nachbur et al. (2012) used the same strain of Bid-null mice as Yeretssian et al. (2012) and found that the mice responded like wildtype mice to NOD ligands and that the levels of NFK-beta or ERK activation cytokine secretion from BID-null bone marrow-derived macrophages (BMDMs) were indistinguishable from the wildtype response. Nachbur et al. (2012) therefore proposed that the nonapoptotic role of BID in inflammation and innate immunity should be reassessed. To understand the discrepancy between their results and those of Yeretssian et al. (2012), Nachbur et al. (2012) generated BMDMs from wildtype, Bid-null, and Ripk2-null mice and activated NOD signaling in these cells in vitro by 2 separate methods. Regardless of the method used, Nachbur et al. (2012) observed comparable levels of IL6 (147620) secretion in Bid-null and wildtype BMDMs, whereas Ripk2-null cells were unresponsive to any of the treatments. Nachbur et al. (2012) evaluated activation of NFK-beta and ERK signaling using 4 different protocols for NOD activation and, regardless of method, detected normal levels of NFK-beta activation and ERK phosphorylation in Bid-deficient BMDMs. They concluded that BID is not essential for NOD signaling. Yeretssian et al. (2012) replied that it is difficult to draw any conclusions based on the divergent data presented by Nachbur et al. (2012) and that although the extent to which BID is required for NOD signaling may vary with cellular context and with environmental and disease conditions, their conclusion that BID contributes to NOD-mediated responses is reproducible and has been repeated independently.
Keestra et al. (2013) demonstrated that NOD1 senses cytosolic microbial products by monitoring the activation state of small Rho GTPases. Activation of RAC1 (602048) and CDC42 (116952) by bacterial delivery or ectopic expression of SopE, a virulence factor of the enteric pathogen Salmonella, triggered the NOD1 signaling pathway with consequent RIP2 (603455)-mediated induction of NF-kappa-B (see 164011)-dependent inflammatory responses. Similarly, activation of the NOD1 signaling pathway by peptidoglycan required RAC1 activity. Furthermore, Keestra et al. (2013) showed that constitutively active forms of RAC1, CDC42, and RHOA (165390) activated the NOD1 signaling pathway.
Using mouse and human cells, Keestra-Gounder et al. (2016) identified NOD1 and NOD2 as mediators of inflammation induced by endoplasmic reticulum (ER) stress. Induction of ER stress triggered IL6 production in an NOD1/NOD2-dependent manner. Infection of mice with Brucella abortus, which induces ER stress in a TLR-independent manner, triggered inflammation and Il6 production in a Traf2 (601895)-, Nod1/Nod2-, and Rip2-dependent manner. B. abortus-induced inflammation and Il6 production could be reduced by treatment with an ER-stress inhibitor or an Ire1a (ERN1; 604033) kinase inhibitor. Keestra-Gounder et al. (2016) concluded that an NOD1/NOD2-dependent pathway mediates ER-stress-induced proinflammatory responses, providing a link between NOD1, NOD2, and inflammatory diseases involving ER stress, such as Crohn disease and type-2 diabetes (NIDDM; 125853).
Watanabe et al. (2010) showed that NOD1, activated by its ligand muropeptide, induces epithelial cells to produce large amounts of proinflammatory chemokines through a pathway that is dependent on activation of the serine-threonine kinase RICK (RIPK2; 603455) and results in the production of type I interferon (e.g., IFNA1, 147660). They found that NOD1 ligand stimulation of epithelial cells enhances the production of chemokines IP10 (CXCL10; 147310) and ITAC (CXCL11; 604852), in the presence or absence of IFN-gamma (147570), but such enhancement was limited to chemokines associated with cytokines that participate in the Th1 response. Analysis of the molecular interactions that facilitate RICK-induced IP10 production revealed that RICK interacts with TRAF3 (601896), which leads to the activation of TRAF3 downstream components TBK1 (604834) and IKK-epsilon (605048). This leads to the activation of IRF7 (605047) and the production of IFN-beta (147640), which then activates the ISGF3 complex (STAT1, 600555; STAT2, 600556; and IRF9, 147574), which induces transcription of IP10.
Hysi et al. (2005) noted that microbial exposures in childhood protect against asthma (600807) through unknown mechanisms. and that the innate immune system is able to identify microbial components through a variety of PRRs, including NOD1, which is an intracellular PRR that initiates inflammation in response to bacterial diaminopimelic acid. Hysi et al. (2005) found an insertion-deletion polymorphism (ND1+32656) near the beginning of intron 9 that accounted for approximately 7% of the variation in total serum IgE (see 147050) in 2 panels of families. The insertion allele was associated with high IgE levels as well as with asthma in an independent study of 600 asthmatic children and 1,194 super-normal controls. Hysi et al. (2005) hypothesized that intracellular recognition of specific bacterial products may affect the presence of childhood asthma.
The identification of the role of genetic variants within NOD2 (CARD15) in susceptibility to inflammatory bowel disease (IBD; see 266600), either Crohn disease or ulcerative colitis, highlights the role of the innate immune system in IBD pathogenesis. McGovern et al. (2005) identified strong association between haplotypes in the terminal exons of NOD1 and inflammatory bowel disease (multiallelic p = 0.0000003) in a panel of 556 IBD trios. The deletion allele of a complex functional NOD1 indel polymorphism (ND1+32656*1; partially identified as rs6958571) was significantly associated with early-onset IBD (p = 0.0003) in unrelated cases and controls.
Using a population genetics approach to define the ways in which natural selection has driven evolution of NOD-like microbial receptors (NLRs) in various human populations, Vasseur et al. (2012) identified 2,084 SNPs, including 396 nonsynonymous SNPs, 4 nonsense variants, and 12 coding region insertion/deletions. Overall, members of the NALP subfamily, which includes NLRP1 (606636) through NLRP14 (609665), had undergone strong purifying selection with little functional diversity. In contrast, members of the NOD/IPAF subfamily, which includes NOD1 through NOD4 (NLRC5; 613537), as well as NOD9 (NLRX1; 611947), CIITA (MHC2TA; 600005), and NLRC4 (606831), had undergone weak negative selection. After expanding their studies to include other major families of microbial sensors, Vasseur et al. (2012) distinguished 3 groups of innate immunity genes that differed in their evolutionary patterns: those under strong selective constraints (most NALPs and endosomal Toll-like receptors (e.g., TLR3; 603029)), those under weaker constraints (most NOD/IPAFs and cytosolic RIGI-like receptors (e.g., DDX58; 609631)), and those that did not appear to deviate from neutrality (most cell surface Toll-like receptors (e.g., TLR1; 601194)).
Using Nod1 -/- mice, Clarke et al. (2010) showed that gut bacterial flora (the microbiota) were a source of peptidoglycan that systemically primed the innate immune system and enhanced killing by bone marrow-derived neutrophils, and that this required Nod1. Enhancement of neutrophil function correlated with serum peptidoglycan concentration. Restoration of neutrophil function after microbiota depletion could be accomplished by administration of Nod1 ligands. Nod1 -/- mice were more susceptible than wildtype mice to pneumococcal sepsis. Clarke et al. (2010) concluded that microbiota depletion through broad-spectrum antibiotics may have adverse consequences for the innate immune response to infection.
T helper-17 (Th17) cells are a subset of CD4 (186940)-positive helper T cells characterized by secretion of IL17 (603149) and IL22 (605330). Geddes et al. (2011) infected mice with Citrobacter rodentium or Salmonella typhimurium species and observed triggering of early Il17 production that was crucial for host defense mediated by Cd4-positive helper T cells. Th17 responses occurred principally in the cecum and were mediated by innate Th17 cells that were regulated by Nod1 and Nod2. Mice lacking both Nod1 and Nod2 were unable to induce early Th17 responses due to insufficient Il6 (147620) production. Geddes et al. (2011) concluded that the NOD-innate Th17 axis, which is dependent on IL6 expression and requires intestinal microbiota for induction, is a key element of mucosal immunity against bacterial pathogens.
Chaves de Souza et al. (2016) studied mice lacking Nod1 in a microbe-induced periodontitis model. Using microcomputed tomography, they found that loss of Nod1 significantly aggravated bone resorption induced by gram-negative bacteria, with an increase in osteoclast numbers. The effect was significantly attenuated in response to gram-positive bacteria. Chaves de Souza et al. (2016) proposed that NOD1 plays a bone-sparing role in this periodontitis model, possibly by reducing expression of proinflammatory mediators.
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