Caspase-1 initiates apoptosis in the absence of gasdermin D

Kohsuke Tsuchiya; Shinsuke Nakajima; Shoko Hosojima; Dinh Thi Nguyen; Tsuyoshi Hattori; Thuong Manh Le; Osamu Hori; Mamunur Rashid Mahib; Yoshifumi Yamaguchi; Masayuki Miura; Takeshi Kinoshita; Hiroko Kushiyama; Mayumi Sakurai; Toshihiko Shiroishi; Takashi Suda

doi:10.1038/s41467-019-09753-2

Caspase-1 initiates apoptosis in the absence of gasdermin D

Nat Commun. 2019 May 7;10(1):2091. doi: 10.1038/s41467-019-09753-2.

Authors

Kohsuke Tsuchiya^{1

2}, Shinsuke Nakajima³, Shoko Hosojima³, Dinh Thi Nguyen⁴, Tsuyoshi Hattori⁴, Thuong Manh Le⁴, Osamu Hori⁴, Mamunur Rashid Mahib³, Yoshifumi Yamaguchi⁵, Masayuki Miura⁶, Takeshi Kinoshita³, Hiroko Kushiyama³, Mayumi Sakurai³, Toshihiko Shiroishi⁷, Takashi Suda⁸

Affiliations

¹ Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. ktsuchiya@staff.kanazawa-u.ac.jp.
² Institute for Frontier Science Initiative (InFiniti), Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. ktsuchiya@staff.kanazawa-u.ac.jp.
³ Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
⁴ Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takara-Machi, Kanazawa, 920-8640, Japan.
⁵ Institute of Low Temperature Science, Hokkaido University, Kita-19, Nishi-8, Kita-ku, Sapporo, 060-0819, Japan.
⁶ Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
⁷ Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka, 411-8540, Japan.
⁸ Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. sudat@staff.kanazawa-u.ac.jp.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
BH3 Interacting Domain Death Agonist Protein / genetics
BH3 Interacting Domain Death Agonist Protein / metabolism
Caspase 1 / physiology*
Caspase 3 / metabolism
Caspase 9 / metabolism
Cell Line, Tumor
Cerebral Cortex / cytology
Embryo, Mammalian
Gene Knockout Techniques
Inflammasomes / immunology*
Intracellular Signaling Peptides and Proteins
Macrophages / cytology
Macrophages / immunology
Macrophages / microbiology
Mice
Mice, Inbred C57BL
Neurons / drug effects
Neurons / physiology
Nigericin / pharmacology
Phosphate-Binding Proteins
Primary Cell Culture
Pyroptosis / drug effects
Pyroptosis / immunology*
RAW 264.7 Cells
Receptors, Estrogen / metabolism*
Salmonella typhimurium / immunology

Substances

Apoptosis Regulatory Proteins
BH3 Interacting Domain Death Agonist Protein
Bid protein, mouse
Gsdmd protein, mouse
Gsdme protein, mouse
Inflammasomes
Intracellular Signaling Peptides and Proteins
Phosphate-Binding Proteins
Receptors, Estrogen
Casp3 protein, mouse
Casp9 protein, mouse
Caspase 3
Caspase 9
Casp1 protein, mouse
Caspase 1
Nigericin