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

Corey Rogers, Dan A. Erkes, Alexandria Nardone, Andrew E. Aplin, Teresa Fernandes-Alnemri () and Emad S. Alnemri ()
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Corey Rogers: Thomas Jefferson University
Dan A. Erkes: Thomas Jefferson University
Alexandria Nardone: Thomas Jefferson University
Andrew E. Aplin: Thomas Jefferson University
Teresa Fernandes-Alnemri: Thomas Jefferson University
Emad S. Alnemri: Thomas Jefferson University

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09397-2

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