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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Corey Rogers & Dan A. Erkes & Alexandria Nardone & Andrew E. Aplin & Teresa Fernandes-Alnemri & Emad S. Alnemri, 2019. "Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09397-2
    DOI: 10.1038/s41467-019-09397-2
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    Cited by:

    1. Fengxia Ma & Laxman Ghimire & Qian Ren & Yuping Fan & Tong Chen & Arumugam Balasubramanian & Alan Hsu & Fei Liu & Hongbo Yu & Xuemei Xie & Rong Xu & Hongbo R. Luo, 2024. "Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Yangci Liu & Haoming Zhai & Helen Alemayehu & Jérôme Boulanger & Lee J. Hopkins & Alicia C. Borgeaud & Christina Heroven & Jonathan D. Howe & Kendra E. Leigh & Clare E. Bryant & Yorgo Modis, 2023. "Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Zhu, Ligang & Li, Xiang & Xu, Fei & Yin, Zhiyong & Jin, Jun & Liu, Zhilong & Qi, Hong & Shuai, Jianwei, 2022. "Network modeling-based identification of the switching targets between pyroptosis and secondary pyroptosis," Chaos, Solitons & Fractals, Elsevier, vol. 155(C).
    4. Yuanyuan Wei & Beidi Lan & Tao Zheng & Lin Yang & Xiaoxia Zhang & Lele Cheng & Gulinigaer Tuerhongjiang & Zuyi Yuan & Yue Wu, 2023. "GSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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