Caspase-2 kills cells with extra centrosomes
Rizzotto et al., Sci. Adv. 10, eado6607 (2024) 30 October 2024 (Impact Factor 14.136)
Centrosomes are membrane-less organelles that orchestrate a wide array of biological functions by acting as microtubule organizing centers. Here, we report that caspase-2–driven apoptosis is elicited in blood cells failing cytokinesis and that extra centrosomes are necessary to trigger this cell death. Activation of caspase-2 depends on the PIDDosome multi-protein complex, and priming of PIDD1 at extra centrosomes is necessary for pathway activation. Accordingly, loss of its centrosomal adapter, ANKRD26, allows for cell survival and unrestricted polyploidization in response to cytokinesis failure. Mechanistically, cell death is initiated upstream of mitochondria via caspase-2–mediated processing of the BCL2 family protein BID, driving BAX/BAK-dependent mitochondrial outer membrane permeabilization (MOMP). Remarkably, BID-deficient cells enforce apoptosis by engaging p53-dependent proapoptotic transcriptional responses initiated by caspase-2. Consistently, BID and MDM2 act as shared caspase-2 substrates, with BID being kinetically favored. Our findings document that the centrosome limits its own unscheduled duplication by the induction of PIDDosome-driven mitochondrial apoptosis to avoid potentially pathogenic polyploidization events.
Dario Rizzotto 1†, Vincenza Vigorito 2†, Patricia Rieder1, Filip Gallob1, Gian Mario Moretta2,Claudia Soratroi3, Joel S. Riley 3, Florian Bellutti2, Stefano Li Veli2, Alessia Mattivi2,Michael Lohmüller3‡, Sebastian Herzog3, Beat C. Bornhauser4, Etienne D. Jacotot5,6,Andreas Villunger 1,3*, Luca L. Fava2*
1 ceMM Research center for Molecular Medicine of the Austrian Academy of Sciences, 1090 vienna, Austria. 2 Armenise-harvard laboratory of cell division, department of cellular, computational and integrative Biology-ciBiO, University of trento,trento, italy. 3 institute for developmental immunology, Biocenter, Medical University innsbruck, 6020 innsbruck, Austria. 4 department of Oncology and children’sResearch centre, University children’s hospital Zürich, 8032 Zürich, Switzerland.5 inserm U1268, Medicinal chemistry and translational Research, Paris F-75006,France. 6 Faculté de Pharmacie, UMR 8038 citcoM, Université Paris cité, Paris F-75006, France.
American Association for the Advancement of Science
October 30, 2024