Large transient assemblies of Apaf1 constitute the apoptosome in cells
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.
Authors
- Joel S. Riley (ORCID: https://orcid.org/0000-0001-9170-5716)
- Stephen W. G. Tait (ORCID: https://orcid.org/0000-0001-7697-132X)
- Alicia C. Borgeaud (ORCID: https://orcid.org/0000-0002-7231-7424)
- Wanda Kukulski (ORCID: https://orcid.org/0000-0002-2778-3936)
- Thomas Kaufmann (ORCID: https://orcid.org/0000-0001-9906-874X)
- Calvin Klein (ORCID: https://orcid.org/0000-0002-0932-7240)
- Liyang Wu (ORCID: https://orcid.org/0000-0001-6930-1993)
- Daniela Ross‐Kaschitza (ORCID: https://orcid.org/0000-0003-1367-0671)
- Thomas Lemmin (ORCID: https://orcid.org/0000-0001-5705-4964)
- Iva Ganeva (ORCID: https://orcid.org/0000-0003-3221-2502)
- Amandine Stooss
Institutions
- University of Bern (CH)
- Innsbruck Medical University (AT)
- MRC Laboratory of Molecular Biology (GB)
- Universität Innsbruck (AT)
- Cancer Research UK (GB)
- Universidad Iberoamericana (DO)
- University of Glasgow (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-24
- DOI
- https://doi.org/10.1038/s41467-025-64478-9
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Novartis Foundation
- University of Bern
- UK Research and Innovation
- Cancer Research UK
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Novartis Stiftung für Medizinisch-Biologische Forschung
- Medical Research Council