2. Academic Validation
  3. Caspase-1 initiates apoptosis in the absence of gasdermin D

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.
Kohsuke Tsuchiya 1 2,  Shinsuke Nakajima 3,  Shoko Hosojima 3,  Dinh Thi Nguyen 4,  Tsuyoshi Hattori 4,  Thuong Manh Le 4,  Osamu Hori 4,  Mamunur Rashid Mahib 3,  Yoshifumi Yamaguchi 5,  Masayuki Miura 6,  Takeshi Kinoshita 3,  Hiroko Kushiyama 3,  Mayumi Sakurai 3,  Toshihiko Shiroishi 7,  Takashi Suda 8
Affiliations

Affiliations

  • 1 Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. [email protected].
  • 2 Institute for Frontier Science Initiative (InFiniti), Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. [email protected].
  • 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. [email protected].
PMID: 31064994 DOI: 10.1038/s41467-019-09753-2
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.

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