G Protein Signaling Modulator-3 Inhibits the Inflammasome Activity of NLRP3

Giguère, Patrick M.; Gall, Bryan; Ezekwe, Ejiofor A.D.; Laroche, Geneviève; Buckley, Brian K.; Kébaïer, Chahnaz; Wilson, Justin E.; Ting, Jenny P.Y.; Siderovski, David P.; Duncan, Joseph A.

doi:10.1074/jbc.m114.578393

Cited by 28 publications

(20 citation statements)

References 53 publications

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“…However, many of the interacting SNPs are located near or within genes that may be involved in, or interfere with, mucosal barrier function (e.g. NOD2 , IRGM , CDH1 and GPSM3 36 ) or the adaptive immune response (e.g. IL2RA , CCL11 , CCL8 , MICB, IL10 and the HLA region).…”

Section: Discussionmentioning

confidence: 99%

Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice

et al. 2017

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BACKGROUND & AIMS The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene–smoking interactions) that affect risk for Crohn’s disease (CD) and ulcerative colitis (UC) in a case-only study of patients and in mouse models of IBD. METHODS We used 55 immunochip-wide data sets that included 19,735 IBD cases (10,856 CD cases and 8879 UC cases) of known smoking status. We performed 3 meta-analyses each for CD, UC, and IBD (CD and UC combined), comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers. We studied the effects of exposure to cigarette smoke in Il10−/− and Nod2−/− mice, as well as in Balb/c mice without disruption of these genes (wild-type mice). Mice were exposed to the smoke of 5 cigarettes per day, 5 days a week, for 8 weeks, in a ventilated smoking chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription PCR. RESULTS We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta-analysis Wald test P<5.0×10−5; heterogeneity Cochrane Q test P>.05). Twenty of these variants were located within the HLA region at 6p21. Analysis of classical HLA alleles (imputed from SNP genotypes) revealed an interaction with smoking. We replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for CD (frameshift variant fs1007insC; rs5743293). We identified 2 variants in the same genomic region (rs2270368 and rs17221417) that interact with smoking in relation to CD risk. Approximately 45% of the SNPs that interact with smoking were in close vicinity (≤1 Mb) to SNPs previously associated with IBD; many were located near or within genes that regulate mucosal barrier function and immune tolerance. Smoking modified the disease risk of some variants in opposite directions for CD vs UC. Exposure of IL10-deficient mice to cigarette smoke accelerated development of colitis and increased expression of interferon gamma in the small intestine, compared to wild-type mice exposed to smoke. NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wildtype mice exposed to smoke. CONCLUSION In an analysis of 55 immunochip-wide data sets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene–smoking interactions were confirmed in mice with disruption of Il10 and Nod2—variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants.

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Section: Discussionmentioning

confidence: 99%

Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice

et al. 2017

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“…This could alter the rate of degradation of AGS4/GPSM3 protein and could be one contributing factor leading to the inability to detect this protein in the kidney sections. For this reason, AGS4/GPSM3 has been largely studied in other cell types, particularly immune cells, due to its relatively high expression levels (Cao, Cismowski 2004, Billard, Gall 2014). Functionally, there is evidence that AGS4/GPSM3 couples to Gαi subunits to modulate agonist-dependent G-protein coupled receptor signaling (Oner, Maher 2010).…”

Section: Discussionmentioning

confidence: 99%

“…However, the biological relevance of Group I and II AGS in the kidney requires further investigation in genetically modified animal models. At present, mouse models that are genetically deficient for AGS1 (Cha, Kim 2013, Chen, Khan 2013, Cheng, Obrietan 2004), AGS3 (Regner, Nozu 2011, Blumer, Lord 2008), AGS4 (Giguere, Billard 2013, Giguere, Gall 2014), AGS5 (Konno, Shioi 2008) and AGS6 (Yang, Li 2013) are available, so there is opportunity exists to determine whether changes in the AGS gene expression can play a crucial role during various pathologies in the kidney.…”

Section: Discussionmentioning

confidence: 99%

Localization and expression profile of Group I and II Activators of G-protein Signaling in the kidney

et al. 2014

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Activators of G-protein Signaling (AGS) are a family of accessory proteins that were discovered as modulators of heterotrimeric G-protein subunits. The primary aim of the present study was to localize Group I and II AGS proteins and determine the renal expression profile using immunohistochemistry and quantitative RT-PCR, respectively, during normal and injured states of the kidney. Group I AGS1 was found to be predominantly localized to the proximal tubule, Group II AGS3 and AGS5 were exclusively localized to the distal tubular segments, and Group II AGS6 was ubiquitously expressed in every nephron segment of the rodent kidney. In rat kidneys following ischemia-reperfusion injury (IRI), Group I AGS1 mRNA was dramatically increased after 24 hours by 5-fold (P<0.05), whereas Group II AGS3 and AGS4 mRNA was significantly decreased at the same time point (P<0.05). No significant change in the transcript levels were detected at other time points for any of the AGS genes between control and IRI groups. In polycystic diseased kidneys, mRNA levels for AGS3, AGS4 and AGS6 was significantly increased (P<0.05) by 75–80% in PCK rat kidneys. The identification of Group I and II AGS mRNA and protein in the kidney may provide insight into the potential mechanism of action during normal and varying states of renal disease or injury.

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“…126 Recent studies using a yeast twohybrid screen showed that the hematopoietic-restricted G protein signaling modulator-3 (GPSM3) interacts with NLRP3 and acts as a negative regulator of IL-1b production in response to NLRP3-dependent inflammasome activators. 127 In the screening of a kinase inhibitor library in another recent study, 3,4-methylenedioxy-b-nitrostyrene (MNS) was identified by the prevention of NLRP3-mediated ASC speck formation through targeting NLRP3 or NLRP3-associated complexes. 128 It is also noted that caspase-1, in spite of its essential role in the assembly of NLRP3 inflammasome, is found to play a critical regulatory role in house dust mite-induced allergic lung inflammation through downregulation of IL-33.…”

Section: Negative Regulation Of Nlrp3 Inflammasome Complex Activationmentioning

confidence: 99%

Molecular mechanisms regulating NLRP3 inflammasome activation

et al. 2015

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G Protein Signaling Modulator-3 Inhibits the Inflammasome Activity of NLRP3

Cited by 28 publications

References 53 publications

Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice

Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice

Localization and expression profile of Group I and II Activators of G-protein Signaling in the kidney

Molecular mechanisms regulating NLRP3 inflammasome activation

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