GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA789330 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17244044.fastq.gz | Fastqsanger.gz | |||
| SRR17244045.fastq.gz | Fastqsanger.gz | |||
| SRR17244046.fastq.gz | Fastqsanger.gz | |||
| SRR17244047.fastq.gz | Fastqsanger.gz | |||
| SRR17244048.fastq.gz | Fastqsanger.gz |
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Project description:Gasdermins are a family of structurally-related proteins originally described for their role in pyroptosis. Gasdermin B (GSDMB) is currently the least studied, and while its association with genetic susceptibility to chronic, mucosal inflammatory disorders is well-established, little is known of its functional relevance during active disease states. Herein, we report increased GSDMB in inflammatory bowel disease, with single-cell analysis identifying epithelial specificity to inflamed colonocytes/crypt top colonocytes. Surprisingly, mechanistic experiments and transcriptome profiling reveal lack of inherent GSDMB-dependent pyroptosis in activated epithelial cells and organoids, but instead, point to increased proliferation and migration during in vitro wound closure, which arrests in GSDMB-deficient cells that display hyper-adhesiveness and enhanced formation of vinculin-based actomyosin stress fibers dependent on PDGF-A-mediated FAK phosphorylation. Importantly, carriage of disease-associated GSDMB SNPs confers functional defects disrupting epithelial restitution/repair, which altogether, establishes GSDMB as a critical factor for restoration of epithelial barrier function and the resolution of inflammation.
2022-01-30 | GSE191015 | GEO
Project description:Gasdermins are a family of structurally related proteins originally described for their role in pyroptosis. Gasdermin B (GSDMB) is currently the least studied, and while its association with genetic susceptibility to chronic mucosal inflammatory disorders is well established, little is known about its functional relevance during active disease states. Herein, we report increased GSDMB in inflammatory bowel disease, with single-cell analysis identifying epithelial specificity to inflamed colonocytes/crypt top colonocytes. Surprisingly, mechanistic experiments and transcriptome profiling reveal lack of inherent GSDMB-dependent pyroptosis in activated epithelial cells and organoids but instead point to increased proliferation and migration during in vitro wound closure, which arrests in GSDMB-deficient cells that display hyper-adhesiveness and enhanced formation of vinculin-based focal adhesions dependent on PDGF-A-mediated FAK phosphorylation. Importantly, carriage of disease-associated GSDMB SNPs confers functional defects, disrupting epithelial restitution/repair, which, altogether, establishes GSDMB as a critical factor for restoration of epithelial barrier function and the resolution of inflammation.
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Project description:To determine the transcriptional programs initiated by IFN-λ to delay tissue restitution, we isolated intestinal crypts from the small intestine of VilCREIfnlr1fl/fl mice or WT littermates that have been irradiated and performed targeted transcriptomics analysis
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Project description:Type III interferons induce pyroptosis in gut epithelial cells and delay tissue restitution upon intestinal injury
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Project description:Type III interferons induce pyroptosis in gut epithelial cells and delay tissue restitution upon acute intestinal injury.
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Project description:Tissue damage and repair are hallmarks of inflammation. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight on how inflammation affects repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa. We found that type III, not type I or II, interferons delay epithelial cell regeneration by inducing the upregulation of Z-DNA-binding protein 1 (ZBP1). Z-nucleic acids formed following intestinal damage are sensed by ZBP1, leading to Caspase-8 activation, and cleavage of Gasdermin C (GSDMC). Cleaved GSDMC drives epithelial cell death by pyroptosis and delays repair of the large or small intestine after colitis or irradiation, respectively. The type III interferon/ZBP1/Caspase-8/GSDMC axis is also active in patients with inflammatory bowel disease (IBD). Our findings highlight the capacity of type III interferons to delay gut repair, which has important implications for IBD patients or individuals exposed to radiation therapies.
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Project description:Tissue damage and repair are hallmarks of the inflammatory process. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight on how inflammatory mediators affect repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa driven by inflammation or genotoxicity. We found that type III, but not type I or II, interferons delay epithelial cell regeneration by inducing the upregulation of Z-DNA-binding protein 1 (ZBP1). Z-nucleic acids formed during the damage and repair process are then sensed by ZBP-1, leading to Caspase-8 activation, and cleavage of Gasdermin C (GSDMC). Cleaved GSDMC drives epithelial cell death by pyroptosis and delays the re-epithelialization of the large or small intestine after colitis or irradiation, respectively. We also found that the type III interferon/ZBP1/Caspase-8/GSDMC pathway is activated in patients with inflammatory bowel disease (IBD). Our findings highlight a molecular signaling cascade initiated by type III interferons that delays intestinal tissue repair, which has important implications for IBD patients or individuals exposed to radiation therapies.
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Project description:Corneal wound healing involves complex cellular processes, including keratocyte cell death, which plays a pivotal role in initiating tissue repair. Recent studies suggest that pyroptosis, characterized by the release of pro-inflammatory factors, occurs during tissue repair which may also contribute to the inflammatory phase of corneal wound healing. In this study, we investigated the nature of cell death in human keratocytes treated with nigericin, a known pyroptosis inducer. Surprisingly, nigericin triggered a unique form of non-inflammatory cell death marked by extensive vacuolation, resembling paraptosis. Proteomic analysis revealed that our human keratocytes lack key components of the canonical pyroptosis pathway, including NLRP3, ASC, and caspase-1, potentially explaining the absence of pyroptosis in these cells. This process was further confirmed by the absence of caspase-3 activation and lack of ER stress, alongside increased autophagic marker LC3-II accumulation. These findings suggest that nigericin triggers a paraptosis-like cell death in keratocytes, rather than pyroptosis, highlighting an alternative mechanism of cell death in corneal wound healing that warrants further exploration.
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