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The PIDDosome controls cardiomyocyte polyploidization during postnatal heart development

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Publicado en:bioRxiv (Feb 19, 2025)
Autor principal: Leone, Marina
Otros Autores: Eichin, Felix, Kinz, Nadine, Obwegs, David, Sladky, Valentina C, Rizzotto, Dario, Manzl, Claudia, Moos, Katharina, Mergner, Julia, Savko, Clarissa, Giansanti, Piero, Nicole Martinez Garcia, Marques, Margarita M, Jacotot, Etienne D, Boerries, Melanie, Sussman, Mark, Villunger, Andreas
Publicado:
Cold Spring Harbor Laboratory Press
Materias:
p53 Protein
Polyploidy
Cell differentiation
Caspase-2
Heart
Structure-function relationships
Cardiomyocytes
Ploidy
Centrioles
Postpartum period
Cell cycle
Acceso en línea:Citation/Abstract
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Resumen:The adult mammalian heart is characterized by post-mitotic polyploid cardiomyocytes (CMs). Understanding how CMs regulate cell cycle exit and ploidy can help developing new heart regenerative therapies. Here, we uncover that the PIDDosome, a multi-protein complex activating the endopeptidase Caspase-2, helps to implement a CM-specific differentiation program that limits ploidy during postnatal heart development. DNA content analyses show that PIDDosome-loss causes a cell-autonomous increase in nuclear and cellular CM ploidy. Remarkably, increased ploidy does not affect cardiac structure nor function. PIDDosome-imposed ploidy restriction commences at postnatal day 7 (P7), reaching a plateau on P14. PIDDosome activation requires ANKRD26, targeting PIDD1 to mother centrioles. Opposite to prior observations in liver development, the PIDDosome limits CM polyploidization in a p53-independent manner but reliant on p21/Cdkn1a, a notion supported by nuclear RNA sequencing and genetic deletion experiments. Our results provide new insights how proliferation of polyploid CMs is restricted during postnatal heart development.Competing Interest StatementThe authors have declared no competing interest.Footnotes* We have included additional data, such as N-terminomics, aiming to identify Caspase-2 substrates, we also analyzed p73 KO mice. As a result, we also included additional authors
ISSN:2692-8205
DOI:10.1101/2024.08.27.609375
Fuente:Biological Science Database