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

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…

• TJ
  Thomas Jefferson University
• NI
  National Institutes of Health

  Awards: CA196278, CA182635, AR074564, 5 P30 CA-56036
• NC
  National Cancer Institute

  Awards: 5 P30 CA-56036, CA196278, CA182635, P30 CA-56036, NCI 5 P30 CA-56036
• NI
  National Institute of Arthritis and Musculoskeletal and Skin Diseases

  Awards: AR055398, AR074564