| First Author | Bulek K | Year | 2020 |
| Journal | J Clin Invest | Volume | 130 |
| Issue | 8 | Pages | 4218-4234 |
| PubMed ID | 32597834 | Mgi Jnum | J:293960 |
| Mgi Id | MGI:6452563 | Doi | 10.1172/JCI138103 |
| Citation | Bulek K, et al. (2020) Epithelial-derived gasdermin D mediates nonlytic IL-1beta release during experimental colitis. J Clin Invest 130(8):4218-4234 |
| abstractText | 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-1beta. Here, we report a nonpyroptotic role of full-length GSDMD in guiding the release of IL-1beta-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-1beta, serving as a signal for cargo loading into secretory vesicles. GSDMD and IL-1beta colocalize with the exosome markers CD63 and ALIX intracellularly, and GSDMD and NEDD4 are required for release of CD63+ sEVs containing IL-1beta, 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-1beta-containing sEVs is detected in cultured colonic explants from colitic mice, GSDMD deficiency substantially attenuates disease severity, implicating GSDMD-mediated release of IL-1beta sEVs in the pathogenesis of intestinal inflammation, such as that observed in IBD. |
