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

Corey Rogers1, Dan A Erkes2, Alexandria Nardone1

  • 1Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

Nature Communications
|April 13, 2019
PubMed

Insights

Gasdermin E (GSDME) N-domain triggers mitochondrial damage and apoptosis, unlike its known role in pyroptosis. GSDME deficiency enhances cell growth, suggesting its role in cell death regulation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Gasdermin E (GSDME) cleavage by caspase-3 releases the N-domain (GSDME-N).
  • GSDME-N is known to mediate pyroptosis via plasma membrane pore formation.
  • The role of GSDME in apoptosis and its regulation remains incompletely understood.

Purpose of the Study:

  • To investigate the role of GSDME-N in mitochondrial membrane permeabilization.
  • To explore the impact of GSDME deficiency on apoptosis and cell growth.
  • To identify potential regulatory mechanisms of GSDME activity.

Main Methods:

  • Analysis of cytochrome c release and caspase-3 activation in GSDME-deficient and wild-type cells.
  • Assessment of cell growth in vitro and in a melanoma mouse model.
  • Site-directed mutagenesis to investigate GSDME phosphorylation at Thr6.

Main Results:

  • GSDME-N permeabilizes mitochondrial membranes, releasing cytochrome c and activating the apoptosome.
  • GSDME deficiency significantly reduces cytochrome c release and caspase-3 activation.
  • GSDME deficiency accelerates cell growth in culture and in a melanoma model.
  • Phosphomimetic mutation at Thr6 inhibits GSDME's pore-forming activity.

Conclusions:

  • GSDME plays a crucial role in augmenting the mitochondrial apoptotic pathway by targeting mitochondria.
  • GSDME deficiency promotes cell proliferation, indicating its involvement in cell death regulation.
  • GSDME phosphorylation at Thr6 represents a potential regulatory mechanism for its pore-forming function.

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