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.

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
  • Dfna5h protein, mouse
  • Gsdmd 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