Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation
By Corey Rogers, Dan A Erkes, A. Nardone, A. Aplin, T. Fernandes-Alnemri, E. Alnemri. Nature Communications, 2019
729 citations recorded by the source corpus.
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. Gasdermins mediate lytic cell death by forming pores in the plasma membrane. Here the authors show that gasdermins also permeabilize mitochondrial membrane, thereby facilitating intrinsic apoptosis pathway, downstream of apoptotic (Gasdermin E) and inflammatory (Gasdermin D) caspase activation.
Subfields: Molecular Biology, Molecular Medicine
View Paper: https://www.semanticscholar.org/paper/be8cb7419240f64e91325f9094a42e55adea6335
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Citations in the corpus
- Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “Most members of the GSDM family (A-E) consist of an N-terminal pore-forming domain (PFD) and a C-terminal repressor domain [43, 44].”