Gasdermin D mediates the maturation and release of IL-1α downstream of inflammasomes
Kohsuke Tsuchiya,
Shoko Hosojima,
Hideki Hara,
Hiroko Kushiyama,
Mamunur Rashid Mahib,
Takeshi Kinoshita,
Takashi Suda
Affiliations
Kohsuke Tsuchiya
Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; Institute for Frontier Science Initiative (InFiniti), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; Corresponding author
Shoko Hosojima
Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
Hideki Hara
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
Hiroko Kushiyama
Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
Mamunur Rashid Mahib
Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong-4331, Bangladesh
Takeshi Kinoshita
Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
Takashi Suda
Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; Corresponding author
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.
