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Gasdermin-A3 pore formation propagates along variable pathways

Author

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  • Stefania A. Mari

    (Eidgenössische Technische Hochschule (ETH) Zurich)

  • Kristyna Pluhackova

    (Eidgenössische Technische Hochschule (ETH) Zurich)

  • Joka Pipercevic

    (Biozentrum, University of Basel)

  • Matthew Leipner

    (Eidgenössische Technische Hochschule (ETH) Zurich)

  • Sebastian Hiller

    (Biozentrum, University of Basel)

  • Andreas Engel

    (Eidgenössische Technische Hochschule (ETH) Zurich)

  • Daniel J. Müller

    (Eidgenössische Technische Hochschule (ETH) Zurich)

Abstract

Gasdermins are main effectors of pyroptosis, an inflammatory form of cell death. Released by proteolysis, the N-terminal gasdermin domain assembles large oligomers to punch lytic pores into the cell membrane. While the endpoint of this reaction, the fully formed pore, has been well characterized, the assembly and pore-forming mechanisms remain largely unknown. To resolve these mechanisms, we characterize mouse gasdermin-A3 by high-resolution time-lapse atomic force microscopy. We find that gasdermin-A3 oligomers assemble on the membrane surface where they remain attached and mobile. Once inserted into the membrane gasdermin-A3 grows variable oligomeric stoichiometries and shapes, each able to open transmembrane pores. Molecular dynamics simulations resolve how the membrane-inserted amphiphilic β-hairpins and the structurally adapting hydrophilic head domains stabilize variable oligomeric conformations and open the pore. The results show that without a vertical collapse gasdermin pore formation propagates along a set of multiple parallel but connected reaction pathways to ensure a robust cellular response.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30232-8
    DOI: 10.1038/s41467-022-30232-8
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    References listed on IDEAS

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    1. Petr Broz, 2015. "Caspase target drives pyroptosis," Nature, Nature, vol. 526(7575), pages 642-643, October.
    2. Qinyang Wang & Yupeng Wang & Jingjin Ding & Chunhong Wang & Xuehan Zhou & Wenqing Gao & Huanwei Huang & Feng Shao & Zhibo Liu, 2020. "A bioorthogonal system reveals antitumour immune function of pyroptosis," Nature, Nature, vol. 579(7799), pages 421-426, March.
    3. Jianbin Ruan & Shiyu Xia & Xing Liu & Judy Lieberman & Hao Wu, 2018. "Cryo-EM structure of the gasdermin A3 membrane pore," Nature, Nature, vol. 557(7703), pages 62-67, May.
    4. Donald M. Engelman, 2005. "Membranes are more mosaic than fluid," Nature, Nature, vol. 438(7068), pages 578-580, December.
    5. Jingjin Ding & Kun Wang & Wang Liu & Yang She & Qi Sun & Jianjin Shi & Hanzi Sun & Da-Cheng Wang & Feng Shao, 2016. "Pore-forming activity and structural autoinhibition of the gasdermin family," Nature, Nature, vol. 535(7610), pages 111-116, July.
    6. Yupeng Wang & Wenqing Gao & Xuyan Shi & Jingjin Ding & Wang Liu & Huabin He & Kun Wang & Feng Shao, 2017. "Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin," Nature, Nature, vol. 547(7661), pages 99-103, July.
    7. Jianjin Shi & Yue Zhao & Kun Wang & Xuyan Shi & Yue Wang & Huanwei Huang & Yinghua Zhuang & Tao Cai & Fengchao Wang & Feng Shao, 2015. "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death," Nature, Nature, vol. 526(7575), pages 660-665, October.
    8. 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.
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