GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis

Cell. 2022 Jan 20;185(2):283-298.e17. doi: 10.1016/j.cell.2021.12.024. Epub 2022 Jan 11.


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.

Keywords: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Case-Control Studies
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / metabolism*
  • Inflammatory Bowel Diseases / pathology*
  • Methotrexate / pharmacology
  • Mutation / genetics
  • Phosphorylation / drug effects
  • Polymorphism, Single Nucleotide / genetics
  • Pore Forming Cytotoxic Proteins / metabolism*
  • Pyroptosis* / drug effects
  • Pyroptosis* / genetics
  • Reproducibility of Results
  • Transcriptome / drug effects
  • Transcriptome / genetics
  • Up-Regulation / drug effects
  • Wound Healing / drug effects
  • Wound Healing / genetics


  • GSDMB protein, human
  • Pore Forming Cytotoxic Proteins
  • Focal Adhesion Protein-Tyrosine Kinases
  • Methotrexate