PT  - JOURNAL ARTICLE
AU  - Shixuan Liu
AU  - Ceryl Tan
AU  - Chloe Melo-Gavin
AU  - Kevin G. Mark
AU  - Miriam B. Ginzberg
AU  - Ron Blutrich
AU  - Nish Patel
AU  - Michael Rape
AU  - Ran Kafri
TI  - Large cells activate global protein degradation to maintain cell size homeostasis
AID  - 10.1101/2021.11.09.467936
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.11.09.467936
4099  - http://biorxiv.org/content/early/2021/11/11/2021.11.09.467936.short
4100  - http://biorxiv.org/content/early/2021/11/11/2021.11.09.467936.full
AB  - Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. This tight control of cell size involves both cell size checkpoints (e.g., delaying cell cycle progression for small cells) and size-dependent compensation in rates of mass accumulation (e.g., slowdown of cellular growth in large cells). We previously identified that the mammalian cell size checkpoint is mediated by a selective activation of the p38 MAPK pathway in small cells. However, mechanisms underlying the size-dependent compensation of cellular growth remain unknown. In this study, we quantified global rates of protein synthesis and degradation in naturally large and small cells, as well as in conditions that trigger a size-dependent compensation in cellular growth. Rates of protein synthesis increase proportionally with cell size in both perturbed and unperturbed conditions, as well as across cell cycle stages. Additionally, large cells exhibit elevated rates of global protein degradation and increased levels of activated proteasomes. Conditions that trigger a large-size-induced slowdown of cellular growth also promote proteasome-mediated global protein degradation, which initiates only after growth rate compensation occurs. Interestingly, the elevated rates of global protein degradation in large cells were disproportionately higher than the increase in size, suggesting activation of protein degradation pathways. Large cells at the G1/S transition show hyperactivated levels of protein degradation, even higher than similarly sized or larger cells in S or G2, coinciding with the timing of the most stringent size control in animal cells. Together, these findings suggest that large cells maintain cell size homeostasis by activating global protein degradation to induce a compensatory slowdown of growth.Competing Interest StatementThe authors have declared no competing interest.