Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis
- Stanford University, United States
- Hospital for Sick Children, Canada
- University of Toronto, Canada
- University of California, Berkeley, United States
Abstract
Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of mass accumulation rates (Ginzberg et al., 2018). While we previously identified the p38 MAPK pathway as a key regulator of the mammalian cell size checkpoint (S. Liu et al., 2018), the mechanism of size-dependent growth rate regulation has remained elusive. Here, we quantified global rates of protein synthesis and degradation in cells of varying sizes, both under unperturbed conditions and in response to perturbations that trigger size-dependent compensatory growth slowdown. We found that protein synthesis rates scale proportionally with cell size across cell cycle stages and experimental conditions. In contrast, oversized cells that undergo compensatory growth slowdown exhibit a superlinear increase in proteasome-mediated protein degradation, with accelerated protein turnover per unit mass, suggesting activation of the proteasomal degradation pathway. Both nascent and long-lived proteins contribute to the elevated protein degradation during compensatory growth slowdown, with long-lived proteins playing a crucial role at the G1/S transition. Notably, large G1/S cells exhibit particularly high efficiency in protein degradation, surpassing that of similarly sized or larger cells in S and G2, coinciding with the timing of the most stringent size control in animal cells. These results collectively suggest that oversized cells reduce their growth efficiency by activating global proteasome-mediated protein degradation to promote cell size homeostasis.
Data availability
All data presented in this study are included in the manuscript and supporting files. Source data files have been provided for all figures.
Article and author information
Author details
Funding
Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-05805)
- Ran Kafri
Hospital for Sick Children (Restracomp Graduate Fellowship)
- Shixuan Liu
Hospital for Sick Children (Restracomp Postdoc Fellowship)
- Miriam B Ginzberg
University of Toronto (Open Fellowship)
- Ceryl Tan
National Institute of General Medical Sciences (F32GM120956)
- Kevin G Mark
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2025, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
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Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis
eLife 14:e75393.
https://doi.org/10.7554/eLife.75393
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