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Large transient assemblies of Apaf1 constitute the apoptosome in cells

Author

Listed:
  • Alicia C. Borgeaud

    (University of Bern
    MRC Laboratory of Molecular Biology)

  • Iva Ganeva

    (University of Bern
    MRC Laboratory of Molecular Biology)

  • Calvin Klein

    (University of Bern
    University of Bern)

  • Amandine Stooss

    (University of Bern)

  • Daniela Ross-Kaschitza

    (University of Bern)

  • Liyang Wu

    (University of Bern)

  • Joel S. Riley

    (Cancer Research UK Scotland Institute
    University of Glasgow
    Medical University of Innsbruck)

  • Stephen W. G. Tait

    (Cancer Research UK Scotland Institute
    University of Glasgow)

  • Thomas Lemmin

    (University of Bern)

  • Thomas Kaufmann

    (University of Bern)

  • Wanda Kukulski

    (University of Bern
    MRC Laboratory of Molecular Biology)

Abstract

Upon cell death signals, the apoptotic protease-activating factor Apaf1 and cytochrome c interact to form the apoptosome complex. The apoptosome is crucial for mitochondrial apoptosis, as it activates caspases that dismantle the cell. However, the in vivo assembly mechanism and appearance of the apoptosome remain unclear. We show that upon onset of apoptosis, Apaf1 molecules accumulate into multiple foci per cell. Disassembly of the foci correlates with cell survival. Structurally, Apaf1 foci resemble organelle-sized, cloud-like assemblies. They form through specific interactions with cytochrome c, contain caspase-9, and depend on procaspase-9 expression for their formation. We propose that Apaf1 foci correspond to the apoptosome in cells. Transientness and ultrastructure of Apaf1 foci suggest that the dynamic spatiotemporal organisation of apoptosome components regulates progression of apoptosis.

Suggested Citation

  • Alicia C. Borgeaud & Iva Ganeva & Calvin Klein & Amandine Stooss & Daniela Ross-Kaschitza & Liyang Wu & Joel S. Riley & Stephen W. G. Tait & Thomas Lemmin & Thomas Kaufmann & Wanda Kukulski, 2025. "Large transient assemblies of Apaf1 constitute the apoptosome in cells," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64478-9
    DOI: 10.1038/s41467-025-64478-9
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    References listed on IDEAS

    as
    1. Stefan J. Riedl & Wenyu Li & Yang Chao & Robert Schwarzenbacher & Yigong Shi, 2005. "Structure of the apoptotic protease-activating factor 1 bound to ADP," Nature, Nature, vol. 434(7035), pages 926-933, April.
    2. Jonathan Lopez & Margaux Bessou & Joel S. Riley & Evangelos Giampazolias & Franziska Todt & Tony Rochegüe & Andrew Oberst & Douglas R. Green & Frank Edlich & Gabriel Ichim & Stephen W. G. Tait, 2016. "Mito-priming as a method to engineer Bcl-2 addiction," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    3. Michael R. Wozny & Andrea Luca & Dustin R. Morado & Andrea Picco & Rasha Khaddaj & Pablo Campomanes & Lazar Ivanović & Patrick C. Hoffmann & Elizabeth A. Miller & Stefano Vanni & Wanda Kukulski, 2023. "In situ architecture of the ER–mitochondria encounter structure," Nature, Nature, vol. 618(7963), pages 188-192, June.
    4. 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.
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