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Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

Author

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  • Corey Rogers

    (Kimmel Cancer Center, Thomas Jefferson University)

  • Teresa Fernandes-Alnemri

    (Kimmel Cancer Center, Thomas Jefferson University)

  • Lindsey Mayes

    (Kimmel Cancer Center, Thomas Jefferson University)

  • Diana Alnemri

    (Schreyer Honors College, Pennsylvania State University)

  • Gino Cingolani

    (Kimmel Cancer Center, Thomas Jefferson University)

  • Emad S. Alnemri

    (Kimmel Cancer Center, Thomas Jefferson University)

Abstract

Apoptosis is a genetically regulated cell suicide programme mediated by activation of the effector caspases 3, 6 and 7. If apoptotic cells are not scavenged, they progress to a lytic and inflammatory phase called secondary necrosis. The mechanism by which this occurs is unknown. Here we show that caspase-3 cleaves the GSDMD-related protein DFNA5 after Asp270 to generate a necrotic DFNA5-N fragment that targets the plasma membrane to induce secondary necrosis/pyroptosis. Cells that express DFNA5 progress to secondary necrosis, when stimulated with apoptotic triggers such as etoposide or vesicular stomatitis virus infection, but disassemble into small apoptotic bodies when DFNA5 is deleted. Our findings identify DFNA5 as a central molecule that regulates apoptotic cell disassembly and progression to secondary necrosis, and provide a molecular mechanism for secondary necrosis. Because DFNA5-induced secondary necrosis and GSDMD-induced pyroptosis are dependent on caspase activation, we propose that they are forms of programmed necrosis.

Suggested Citation

  • Corey Rogers & Teresa Fernandes-Alnemri & Lindsey Mayes & Diana Alnemri & Gino Cingolani & Emad S. Alnemri, 2017. "Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14128
    DOI: 10.1038/ncomms14128
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    1. Joo-Hui Han & Rajendra Karki & R. K. Subbarao Malireddi & Raghvendra Mall & Roman Sarkar & Bhesh Raj Sharma & Jonathon Klein & Harmut Berns & Harshan Pisharath & Shondra M. Pruett-Miller & Sung-Jin Ba, 2024. "NINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. 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.
    3. Kei-ichiro Arimoto & Sayuri Miyauchi & Ty D. Troutman & Yue Zhang & Mengdan Liu & Samuel A. Stoner & Amanda G. Davis & Jun-Bao Fan & Yi-Jou Huang & Ming Yan & Christopher K. Glass & Dong-Er Zhang, 2023. "Expansion of interferon inducible gene pool via USP18 inhibition promotes cancer cell pyroptosis," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    4. Hanhan Ning & Shan Huang & Yang Lei & Renyong Zhi & Han Yan & Jiaxing Jin & Zhenyu Hu & Kaimin Guo & Jinhua Liu & Jie Yang & Zhe Liu & Yi Ba & Xin Gao & Deqing Hu, 2022. "Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    5. 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).
    6. 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.
    7. Xionghui Ding & Hiroto Kambara & Rongxia Guo & Apurva Kanneganti & Maikel Acosta-Zaldívar & Jiajia Li & Fei Liu & Ting Bei & Wanjun Qi & Xuemei Xie & Wenli Han & Ningning Liu & Cunling Zhang & Xiaoyu , 2021. "Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    8. Stefania A. Mari & Kristyna Pluhackova & Joka Pipercevic & Matthew Leipner & Sebastian Hiller & Andreas Engel & Daniel J. Müller, 2022. "Gasdermin-A3 pore formation propagates along variable pathways," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    9. Hang Yin & Jian Zheng & Qiuqiu He & Xuan Zhang & Xuzichao Li & Yongjian Ma & Xiao Liang & Jiaqi Gao & Benjamin L. Kocsis & Zhuang Li & Xiang Liu & Neal M. Alto & Long Li & Heng Zhang, 2023. "Insights into the GSDMB-mediated cellular lysis and its targeting by IpaH7.8," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Anja Kopp & Gregor Hagelueken & Isabell Jamitzky & Jonas Moecking & Lisa D. J. Schiffelers & Florian I. Schmidt & Matthias Geyer, 2023. "Pyroptosis inhibiting nanobodies block Gasdermin D pore formation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    11. Jing Lin & Shihui Sun & Kui Zhao & Fei Gao & Renling Wang & Qi Li & Yanlong Zhou & Jing Zhang & Yue Li & Xinyue Wang & Le Du & Shuai Wang & Zi Li & Huijun Lu & Yungang Lan & Deguang Song & Wei Guo & Y, 2023. "Oncolytic Parapoxvirus induces Gasdermin E-mediated pyroptosis and activates antitumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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