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Gasdermin D mediates the maturation and release of IL-1α downstream of inflammasomes

Authors :
Kohsuke Tsuchiya
Shoko Hosojima
Hideki Hara
Hiroko Kushiyama
Mamunur Rashid Mahib
Takeshi Kinoshita
Takashi Suda
Source :
Cell Reports, Vol 34, Iss 12, Pp 108887- (2021)
Publication Year :
2021
Publisher :
Elsevier, 2021.

Abstract

Summary: IL-1α serves as a pro-inflammatory cytokine. Although pro-IL-1α has cytokine activity, proteolytic maturation increases its potency and release from cells. IL-1α maturation occurs in a caspase-1-dependent manner following inflammasome activation. However, pro-IL-1α is not a substrate of caspase-1, and it remains unclear what mediates the maturation of this cytokine downstream of inflammasomes. Here, we show that gasdermin D (GSDMD), an executor of pyroptosis, is required for the rapid induction of IL-1α maturation by non-particulate inflammasome activators. Ablation of GSDMD abrogates the maturation of IL-1α, but not of IL-1β. Inflammasome-induced maturation of IL-1α relies on extracellular Ca2+ and calpains. Ca2+ influx and calpain activation are induced in a GSDMD-dependent manner. Glycine, which inhibits cell lysis, but not GSDMD pore formation, does not affect IL-1α maturation. These results suggest that during inflammasome activation, GSDMD processed by caspase-1 forms plasma membrane pores that mediate Ca2+ influx, resulting in the calpain-dependent maturation of IL-1α.

Details

Language :
English
ISSN :
22111247
Volume :
34
Issue :
12
Database :
Directory of Open Access Journals
Journal :
Cell Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.140791d86a44f1caa2add7a1b0dc4a9
Document Type :
article
Full Text :
https://doi.org/10.1016/j.celrep.2021.108887