Centriole signaling restricts hepatocyte ploidy to maintain liver integrity

Abstract

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.

Exact centriole counts are critical for B cell development but not function

“…Together, these findings place progenitor B cells on the list of cell types that critically depend on the surveillance of exact centriole counts and that respond with apoptosis upon their loss. This feature appears far from universal, as centriole deficiency does not affect developmental, neonatal or compensatory hepatocyte proliferation in mice lacking Plk4 in the liver (Sladky et al ., 2022), nor that of gastrointestinal stem cells in the absence of Sas4 (Xie et al ., 2021). Mechanisms underlying these cell type or tissue-dependent differences remain to be uncovered.…”

Centriole structural integrity defects are a crucial feature of Hydrolethalus Syndrome

“…Hyls1 +/DG mice were generated using CRISPR/Cas9 technology as previously described (Phan et al ., 2022; Sladky et al ., 2022). Briefly, one sgRNA (5’-CTACTCGGTCTATCTTGCCC-3’) was co-injected with a ssDNA repair template (5’-CAGTCTCTTTTGTACTCAAAATATCTGGCTACTCGACCCATTTTTCCCCGGTTTCGGCTTAACTGATCCAGTCTGGGGAG-3’) containing the GAC>GGT modification coding for the amino acid 211 as well as a restriction cut site for Taq1 at the site of the edit.…”

“…Finally, recent work revealed centrioles function as signaling centers that restrict the proliferation of polyploid cells in mammals (Sladky et al, 2020(Sladky et al, , 2022. Centrioles are remarkably stable structures that persist over multiple cell cycles with minimal turnover of their molecular components.…”

“…Second, centrioles function as basal bodies that dock at the plasma membrane and initiate the biogenesis of cilia that have motile or sensory functions (Breslow & Holland, 2019; Nigg & Raff, 2009). Finally, recent work revealed centrioles function as signaling centers that restrict the proliferation of polyploid cells in mammals (Sladky et al ., 2020, 2022). Centrioles are remarkably stable structures that persist over multiple cell cycles with minimal turnover of their molecular components.…”

Caspase-2 kills cells with extra centrosomes

“…Similar to the loss of one of the three PIDDosome components, PIDD1, RAIDD or caspase-2, ANKRD26 deficiency abrogates MDM2 cleavage and p53 pathway activation. This response is engaged in cancerous and immortalized epithelial cell lines that accumulate centrosomes, as well as in primary hepatocytes that undergo scheduled cytokinesis failure during development or regeneration ( 8 , 31 ). Curiously, in tissue culture, cells carrying extra centrosomes are lost over time due to strong counterselection ( 6, 32 ).…”