Caspase-2 kills cells with extra centrosomes.
| Title: | Caspase-2 kills cells with extra centrosomes. |
|---|---|
| Authors: | Rizzotto D; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.; Vigorito V; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.; Rieder P; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.; Gallob F; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.; Moretta GM; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.; Soratroi C; Institute for Developmental Immunology, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria.; Riley JS; Institute for Developmental Immunology, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria.; Bellutti F; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.; Veli SL; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.; Mattivi A; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.; Lohmüller M; Institute for Developmental Immunology, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria.; Herzog S; Institute for Developmental Immunology, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria.; Bornhauser BC; Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, 8032 Zürich, Switzerland.; Jacotot ED; Inserm U1268, Medicinal Chemistry and Translational Research, Paris F-75006, France.; Faculté de Pharmacie, UMR 8038 CiTCoM, Université Paris Cité, Paris F-75006, France.; Villunger A; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.; Institute for Developmental Immunology, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria.; Fava LL; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy. |
| Source: | Science advances [Sci Adv] 2024 Nov; Vol. 10 (44), pp. eado6607. Date of Electronic Publication: 2024 Oct 30. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]- |
| MeSH Terms: | Caspase 2*/metabolism ; Caspase 2*/genetics ; Centrosome*/metabolism ; BH3 Interacting Domain Death Agonist Protein*/metabolism ; BH3 Interacting Domain Death Agonist Protein*/genetics ; Death Domain Receptor Signaling Adaptor Proteins*/metabolism ; Death Domain Receptor Signaling Adaptor Proteins*/genetics ; Mitochondria*/metabolism ; Apoptosis*; Proto-Oncogene Proteins c-mdm2/metabolism ; Proto-Oncogene Proteins c-mdm2/genetics ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Protein p53/genetics ; Mitochondrial Membranes/metabolism ; Humans ; Cysteine Endopeptidases |
| Abstract: | 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. |
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| Substance Nomenclature: | EC 3.4.22.- (Caspase 2); 0 (BH3 Interacting Domain Death Agonist Protein); 0 (Death Domain Receptor Signaling Adaptor Proteins); 0 (PIDD1 protein, human); EC 3.4.22.- (CASP2 protein, human); EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2); 0 (Tumor Suppressor Protein p53); 0 (BID protein, human); EC 2.3.2.27 (MDM2 protein, human); EC 3.4.22.- (Cysteine Endopeptidases) |
| Entry Date(s): | Date Created: 20241030 Date Completed: 20241030 Latest Revision: 20260225 |
| Update Code: | 20260226 |
| PubMed Central ID: | PMC11524169 |
| DOI: | 10.1126/sciadv.ado6607 |
| PMID: | 39475598 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't