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

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

Publication date: Apr 11, 2019

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.

Rogers, C., Erkes, D.A., Nardone, A., Aplin, A.E., Fernandes-Alnemri, T., and Alnemri, E.S. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. 22290. 2019 Nat Commun (10):1.

Concepts Keywords
Apoptosis Apoptosis
Apoptotic Cytochrome c
Caspase 3 Pyroptosis
Cleavage Apoptosome
Cytochrome GSDMD
Inflammasome Inflammasome
Melanoma Cytokines
Mitochondria Caspases
Mitochondrial Apoptosis
Mitochondrial Membrane Cellular processes
Mutation Cell biology
Phosphorylatable Programmed cell death
Plasma Membrane Branches of biology
Pyroptosis Deficiency

Semantics

Type Source Name
gene UNIPROT GSDMD
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
pathway BSID Release
disease MESH DFNA5
disease DOID DFNA5
gene UNIPROT GSDME
pathway BSID Apoptosis

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