Gasdermin D (<i>Gsdmd</i>) is dispensable for mouse intestinal epithelium development

Fujii, Tomoaki; Tamura, Masahito; Tanaka, Shinji; Kato, Yoriko; Yamamoto, Hiromi; Mizushina, Youichi; Shiroishi, Toshihiko

doi:10.1002/dvg.20412

Cited by 40 publications

(30 citation statements)

References 12 publications

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“…The loss-of-function type mouse mutants of Gsdm family genes, such as the Gsdmd KO mice in our previous study and the Gsdma KO mice in this study, show neither morphologic anomaly such as epithelial hyperplasia nor tumor development (Fujii et al 2008). The failure to identify a visible phenotype in the KO mice may be due to functional redundancy with the other genes.…”

Section: Discussionmentioning

confidence: 55%

Functional Conservation of Gsdma Cluster Genes Specifically Duplicated in the Mouse Genome

Tanaka¹,

Mizushina

Kato

et al. 2013

G3 Genes|Genomes|Genetics

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Mouse Gasdermin A3 (Gsdma3) is the causative gene for dominant skin mutations exhibiting alopecia. Mouse has two other Gsdma3-related genes, Gsdma and Gsdma2, whereas human and rat have only one related gene. To date, no skin mutation has been reported for human GSDMA and rat Gsdma as well as mouse Gsdma and Gsdma2. Therefore, it is possible that only Gsdma3 has gain-of-function type mutations to cause dominant skin phenotype. To elucidate functional divergence among the Gsdma-related genes in mice, and to infer the function of the human and rat orthologs, we examined in vivo function of mouse Gsdma by generating Gsdma knockout mice and transgenic mice that overexpress wild-type Gsdma or Gsdma harboring a point mutation (Alanine339Threonine). The Gsdma knockout mice shows no visible phenotype, indicating that Gsdma is not essential for differentiation of epidermal cells and maintenance of the hair cycle, and that Gsdma is expressed specifically both in the inner root sheath of hair follicles and in suprabasal cell layers, whereas Gsdma3 is expressed only in suprabasal layers. By contrast, both types of the transgenic mice exhibited epidermal hyperplasia resembling the Gsdma3 mutations, although the phenotype depended on the genetic background. These results indicate that the mouse Gsdma and Gsdma3 genes share common function to regulate epithelial maintenance and/or homeostasis, and suggest that the function of human GSDMA and rat Gsdma, which are orthologs of mouse Gsdma, is conserved as well.

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Section: Discussionmentioning

confidence: 55%

Functional Conservation of Gsdma Cluster Genes Specifically Duplicated in the Mouse Genome

Tanaka¹,

Mizushina

Kato

et al. 2013

G3 Genes|Genomes|Genetics

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“…GSDMB may be involved in the regulation of the growth and differentiation of epithelial cells 40, 41 . The function of the upstream ORMDL3 gene in humans is not clear.…”

Section: Discussionmentioning

confidence: 99%

Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants

Valk

Duijts

Timpson

et al. 2014

Journal of Allergy and Clinical Immunology

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Background The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes. Objective To identify genetic variants associated with childhood FeNO, and their relation with asthma. Methods FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110). Results We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. Conclusion This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma.

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“…Recently, however, a molecule, gasdermin‐D (GSDMD), has been identified as a critical player in these events. GSDMD is a highly conserved protein in mammals, although its function is unclear . GSDMD is approximately 480 amino acids long with two main domains: an N‐terminal GSDMD‐N domain and a C‐terminal GSDMD‐C domain connected by a linker loop and previously found to be cleaved by caspase‐1 .…”

Section: Non‐canonical Inflammasome Activation During Inflammatory Rementioning

confidence: 99%

“…GSDMD is a highly conserved protein in mammals, although its function is unclear. 70 GSDMD is approximately 480 amino acids long with two main domains: an N-terminal GSDMD-N domain and a C-terminal GSDMD-C domain connected by a linker loop 71 and previously found to be cleaved by caspase-1. 72 Kayagaki et al 73 reported that GSDMD plays an essential role in caspase-11 non-canonical inflammasome-dependent pyroptosis and secretion of IL-1b.…”

Section: Gasdermin D Is a Key Molecule In Caspase-11 Noncanonical Infmentioning

confidence: 99%

Caspase‐11 non‐canonical inflammasome: a critical sensor of intracellular lipopolysaccharide in macrophage‐mediated inflammatory responses

2017

Immunology

185

216

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SummaryInflammatory responses mediated by macrophages are part of the innate immune system, whose role is to protect against invading pathogens. Lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria stimulates an inflammatory response by macrophages. During the inflammatory response, extracellular LPS is recognized by Toll-like receptor 4, one of the pattern recognition receptors that activates inflammatory signalling pathways and leads to the production of inflammatory mediators. The innate immune response is also triggered by intracellular inflammasomes, and inflammasome activation induces pyroptosis and the secretion of pro-inflammatory cytokines such as interleukin-1b (IL-1b) and IL-18 by macrophages. Cysteine-aspartic protease (caspase)-11 and the human orthologues caspase-4/caspase-5 were recently identified as components of the 'non-canonical inflammasome' that senses intracellular LPS derived from Gram-negative bacteria during macrophage-mediated inflammatory responses. Direct recognition of intracellular LPS facilitates the rapid oligomerization of caspase-11/4/5, which results in pyroptosis and the secretion of IL-1b and IL-18. LPS is released into the cytoplasm from Gram-negative bacterium-containing vacuoles by small interferoninducible guanylate-binding proteins encoded on chromosome 3 (GBP chr3 )-mediated lysis of the vacuoles. In vivo studies have clearly shown that caspase-11 À/À mice are more resistant to endotoxic septic shock by excessive LPS challenge. Given the evidence, activation of caspase-11 non-canonical inflammasomes by intracellular LPS is distinct from canonical inflammasome activation and provides a new paradigm in macrophagemediated inflammatory responses.

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Gasdermin D (Gsdmd) is dispensable for mouse intestinal epithelium development

Cited by 40 publications

References 12 publications

Functional Conservation of Gsdma Cluster Genes Specifically Duplicated in the Mouse Genome

Functional Conservation of Gsdma Cluster Genes Specifically Duplicated in the Mouse Genome

Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants

Caspase‐11 non‐canonical inflammasome: a critical sensor of intracellular lipopolysaccharide in macrophage‐mediated inflammatory responses

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