Epithelial-derived gasdermin D mediates nonlytic IL-1? release during experimental colitis.

Gasdermin D (GSDMD) induces pyroptosis via the pore-forming activity of its N-terminal domain, cleaved by activated caspases associated with the release of IL-1?. Here, we report a nonpyroptotic role of full-length GSDMD in guiding the release of IL-1?-containing small extracellular vesicles (sEVs) from intestinal epithelial cells (IECs). In response to ...
caspase-8 inflammasome activation, GSDMD, chaperoned by Cdc37/Hsp90, recruits the E3 ligase, NEDD4, to catalyze polyubiquitination of pro-IL-1?, serving as a signal for cargo loading into secretory vesicles. GSDMD and IL-1? colocalize with the exosome markers CD63 and ALIX intracellularly, and GSDMD and NEDD4 are required for release of CD63+ sEVs containing IL-1?, GSDMD, NEDD4, and caspase-8. Importantly, increased expression of epithelial-derived GSDMD is observed both in patients with inflammatory bowel disease (IBD) and those with experimental colitis. While GSDMD-dependent release of IL-1?-containing sEVs is detected in cultured colonic explants from colitic mice, GSDMD deficiency substantially attenuates disease severity, implicating GSDMD-mediated release of IL-1? sEVs in the pathogenesis of intestinal inflammation, such as that observed in IBD.
Mesh Terms:
Animals, Cell Line, Colitis, Epithelial Cells, Exosomes, Extracellular Vesicles, Inflammatory Bowel Diseases, Interleukin-1beta, Intestinal Mucosa, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Nedd4 Ubiquitin Protein Ligases, Phosphate-Binding Proteins, Tetraspanin 30
J Clin Invest
Date: Dec. 03, 2019
Download Curated Data For This Publication
228998
Switch View:
  • Interactions 36