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

Authors

Corey Rogers, Thomas Jefferson UniversityFollow
Dan A. Erkes, Thomas Jefferson UniversityFollow
Alexandria Nardone, Thomas Jefferson UniversityFollow
Andrew E. Aplin, Thomas Jefferson UniversityFollow
Teresa Fernandes-Alnemri, Thomas Jefferson UniversityFollow
Emad S. Alnemri, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

4-11-2019

Comments

This article has been peer reviewed. It is the author’s final published version in Nature Communications, Volume 10, Issue 1, April 2019, Article number 1689.

The published version is available at https://doi.org/10.1038/s41467-019-09397-2. Copyright © Rogers et al.

Publication made possible in part by support from the Thomas Jefferson University + Philadelphia University Open Access Fund

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.

Recommended Citation

Rogers, Corey; Erkes, Dan A.; Nardone, Alexandria; Aplin, Andrew E.; Fernandes-Alnemri, Teresa; and Alnemri, Emad S., "Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation." (2019). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 150.
https://jdc.jefferson.edu/bmpfp/150

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

30976076

Language

English