Sun, M. S.; Martin, B.; Dembska, J.; Deluz, C.; Suter, D. M.

Protein synthesis and decay rates must be tightly coordinated to ensure proteome homeostasis. How this coordination is established is unknown. Here we use quantitative live cell imaging combined with computational inference to determine how changes in global protein synthesis rates alter protein decay rates. We identified two modes of adaptation hinging on differential responses of the cell cycle to changes in protein synthesis rates. A passive adaptation of protein degradation and dilution rates operates in cells tightly coupling proliferation rate to protein synthesis rates, allowing to partially buffer changes in proteome concentrations with increased loss of short-lived proteins. In contrast, the proliferation rate of mouse embryonic stem cells (mESCs) is hyposensitive to moderate changes in protein synthesis. mESCs uncouple protein degradation and dilution rates and robustly maintain their protein levels. Our work illuminates the complex interplay between protein synthesis, degradation, and cell division to regulate proteome homeostasis.