Journal Article

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

Simmons, Alison, Swaidani, Shadi, Rana, Nitish, Miller-Little, William A., Chen, Xing, Qian, Wen, Corridoni, Daniele, Li, Xiaoxia, McCrae, Keith, Zhao, Junjie, Dubyak, George R., Kang, Zizhen, Willard, Belinda B., Bulek, Katarzyna, Cominelli, Fabio, Pizarro, Theresa T., Tang, Fangqiang, Liao, Yun, Wang, Han, Antanaviciute, Agne

2020

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Biomedical research / Biopsy / Caspase-8 / CD63 antigen / Cell Line / Colitis / Colitis - genetics / Colitis - metabolism / Colitis - pathology / Colon / Datasets / Epithelial cells / Epithelial Cells - metabolism / Epithelial Cells - pathology / Exosomes - genetics / Exosomes - metabolism / Exosomes - pathology / Explants / Extracellular vesicles / Extracellular Vesicles - genetics / Extracellular Vesicles - metabolism / Extracellular Vesicles - pathology / Gasdermins / Hsp90 protein / IL-1β / Inflammasomes / Inflammation / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory Bowel Diseases - genetics / Inflammatory Bowel Diseases - metabolism / Inflammatory Bowel Diseases - pathology / Interleukin-1beta - genetics / Interleukin-1beta - metabolism / Intestinal Mucosa - metabolism / Intestinal Mucosa - pathology / Intestine / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Mice / Mice, Knockout / Nedd4 Ubiquitin Protein Ligases - genetics / Nedd4 Ubiquitin Protein Ligases - metabolism / Pathogenesis / Phosphate-Binding Proteins - genetics / Phosphate-Binding Proteins - metabolism / Pyroptosis / Secretory vesicles / Tetraspanin 30 - genetics / Tetraspanin 30 - metabolism / Ubiquitin-protein ligase