Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation

Nat Commun. 2019 Apr 11;10(1):1689. doi: 10.1038/s41467-019-09397-2.

Abstract

Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that GSDME-N also permeabilizes the mitochondrial membrane, releasing cytochrome c and activating the apoptosome. Cytochrome c release and caspase-3 activation in response to intrinsic and extrinsic apoptotic stimuli are significantly reduced in GSDME-deficient cells comparing with wild type cells. GSDME deficiency also accelerates cell growth in culture and in a mouse model of melanoma. Phosphomimetic mutation of the highly conserved phosphorylatable Thr6 residue of GSDME, inhibits its pore-forming activity, thus uncovering a potential mechanism by which GSDME might be regulated. Like GSDME-N, inflammasome-generated gasdermin D-N (GSDMD-N), can also permeabilize the mitochondria linking inflammasome activation to downstream activation of the apoptosome. Collectively, our results point to a role of gasdermin proteins in targeting the mitochondria to promote cytochrome c release to augment the mitochondrial apoptotic pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 3 / metabolism
  • Cytochromes c / metabolism
  • Fibroblasts
  • Gene Knockout Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Inflammasomes / metabolism*
  • Macrophages
  • Melanoma, Experimental / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / physiology*
  • Mitochondrial Membranes / metabolism
  • Mutation
  • Phosphorylation / physiology
  • Primary Cell Culture
  • Protein Domains / genetics
  • Pyroptosis / physiology*
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Skin Neoplasms / pathology*
  • Threonine / metabolism

Substances

  • GSDME protein, human
  • Gsdme protein, mouse
  • Inflammasomes
  • Receptors, Estrogen
  • Threonine
  • Cytochromes c
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3