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

ABSTRACT: 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.

SUBMITTER: Bulek K 

PROVIDER: S-EPMC7410065 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature