Centriole signaling restricts hepatocyte ploidy to maintain liver integrity.
ANKRD26
PIDDosome
TP53
centrioles
distal appendage
liver
polyploidy
Journal
Genes & development
ISSN: 1549-5477
Titre abrégé: Genes Dev
Pays: United States
ID NLM: 8711660
Informations de publication
Date de publication:
18 Aug 2022
18 Aug 2022
Historique:
received:
09
05
2022
accepted:
27
07
2022
entrez:
18
8
2022
pubmed:
19
8
2022
medline:
19
8
2022
Statut:
aheadofprint
Résumé
Hepatocyte polyploidization is a tightly controlled process that is initiated at weaning and increases with age. The proliferation of polyploid hepatocytes in vivo is restricted by the PIDDosome-P53 axis, but how this pathway is triggered remains unclear. Given that increased hepatocyte ploidy protects against malignant transformation, the evolutionary driver that sets the upper limit for hepatocyte ploidy remains unknown. Here we show that hepatocytes accumulate centrioles during cycles of polyploidization in vivo. The presence of excess mature centrioles containing ANKRD26 was required to activate the PIDDosome in polyploid cells. As a result, mice lacking centrioles in the liver or ANKRD26 exhibited increased hepatocyte ploidy. Under normal homeostatic conditions, this increase in liver ploidy did not impact organ function. However, in response to chronic liver injury, blocking centriole-mediated ploidy control leads to a massive increase in hepatocyte polyploidization, severe liver damage, and impaired liver function. These results show that hyperpolyploidization sensitizes the liver to injury, posing a trade-off for the cancer-protective effect of increased hepatocyte ploidy. Our results may have important implications for unscheduled polyploidization that frequently occurs in human patients with chronic liver disease.
Identifiants
pubmed: 35981754
pii: gad.349727.122
doi: 10.1101/gad.349727.122
pmc: PMC9480857
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R01 CA266199
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM114119
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM133897
Pays : United States
Informations de copyright
© 2022 Sladky et al.; Published by Cold Spring Harbor Laboratory Press.
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