Epithelial-derived gasdermin D mediates nonlytic IL-1β 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-1β. Here, we report a nonpyroptotic role of full-length GSDMD in guiding the release of IL-1β–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-1β, serving as a signal for cargo loading into secretory vesicles. GSDMD and IL-1β colocalize with the exosome markers CD63 and ALIX intracellularly, and GSDMD and NEDD4 are required for release of CD63+ sEVs containing IL-1β, 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-1β–containing sEVs is detected in cultured colonic explants from colitic mice, GSDMD deficiency substantially attenuates disease severity, implicating GSDMD-mediated release of IL-1β sEVs in the pathogenesis of intestinal inflammation, such as that observed in IBD.

Source: Journal of Clinical Investigation - June 29, 2020 Category: Biomedical Science Authors: Katarzyna Bulek, Junjie Zhao, Yun Liao, Nitish Rana, Daniele Corridoni, Agne Antanaviciute, Xing Chen, Han Wang, Wen Qian, William A. Miller-Little, Shadi Swaidani, Fangqiang Tang, Belinda B. Willard, Keith McCrae, Zizhen Kang, George R. Dubyak, Fabio Com Source Type: research