Caspase-1 initiates apoptosis in the absence of gasdermin D

Kohsuke Tsuchiya (), Shinsuke Nakajima, Shoko Hosojima, Dinh Nguyen, Tsuyoshi Hattori, Thuong Le, Osamu Hori, Mamunur Rashid Mahib, Yoshifumi Yamaguchi, Masayuki Miura, Takeshi Kinoshita, Hiroko Kushiyama, Mayumi Sakurai, Toshihiko Shiroishi and Takashi Suda ()
Additional contact information
Kohsuke Tsuchiya: Kanazawa University
Shinsuke Nakajima: Kanazawa University
Shoko Hosojima: Kanazawa University
Dinh Nguyen: Kanazawa University
Tsuyoshi Hattori: Kanazawa University
Thuong Le: Kanazawa University
Osamu Hori: Kanazawa University
Mamunur Rashid Mahib: Kanazawa University
Yoshifumi Yamaguchi: Hokkaido University
Masayuki Miura: The University of Tokyo
Takeshi Kinoshita: Kanazawa University
Hiroko Kushiyama: Kanazawa University
Mayumi Sakurai: Kanazawa University
Toshihiko Shiroishi: Genetic Strains Research Center, National Institute of Genetics
Takashi Suda: Kanazawa University

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: Abstract Caspase-1 activated in inflammasomes triggers a programmed necrosis called pyroptosis, which is mediated by gasdermin D (GSDMD). However, GSDMD-deficient cells are still susceptible to caspase-1-mediated cell death. Therefore, here, we investigate the mechanism of caspase-1-initiated cell death in GSDMD-deficient cells. Inflammasome stimuli induce apoptosis accompanied by caspase-3 activation in GSDMD-deficient macrophages, which largely relies on caspase-1. Chemical dimerization of caspase-1 induces pyroptosis in GSDMD-sufficient cells, but apoptosis in GSDMD-deficient cells. Caspase-1-induced apoptosis involves the Bid-caspase-9-caspase-3 axis, which can be followed by GSDME-dependent secondary necrosis/pyroptosis. However, Bid ablation does not completely abolish the cell death, suggesting the existence of an additional mechanism. Furthermore, cortical neurons and mast cells exhibit little or low GSDMD expression and undergo apoptosis after oxygen glucose deprivation and nigericin stimulation, respectively, in a caspase-1- and Bid-dependent manner. This study clarifies the molecular mechanism and biological roles of caspase-1-induced apoptosis in GSDMD-low/null cell types.

Date: 2019
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DOI: 10.1038/s41467-019-09753-2

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