GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis.
Cell
; 185(2): 283-298.e17, 2022 01 20.
Article
en En
| MEDLINE
| ID: mdl-35021065
ABSTRACT
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.
Palabras clave
FAK; GSDMB; GSDMB genetic polymorphisms; Mtx; PDGFA; epithelial organoids; epithelial restitution and repair; focal adhesion kinase; gasdermin B; gasdermins; inflammatory bowel disease; intestinal epithelial cells; methotrexate; platelet-derived growth factor A; resolution of inflammation; single-cell RNA-seq; single-cell profiling
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades Inflamatorias del Intestino
/
Células Epiteliales
/
Proteínas Citotóxicas Formadoras de Poros
/
Piroptosis
Tipo de estudio:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Cell
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos