Core passive and facultative mTOR-mediated mechanisms coordinate mammalian protein synthesis and decay

The maintenance of cellular homeostasis requires tight regulation of proteome concentration and composition. To achieve this, protein production and elimination must be robustly coordinated. However, the mechanistic basis of this coordination remains unclear. Here, we address this question using quantitative live cell imaging, computational modeling, transcriptomics, and proteomics approaches. We found that protein decay rates systematically adapt to global alterations of protein synthesis rates. This adaptation is driven by a core passive mechanism supplemented by facultative changes in mTOR signaling. Passive adaptation hinges on changes in the production rate of the machinery governing protein decay and allows partial maintenance of the cellular proteome. Sustained changes in mTOR signaling provide an additional layer of adaptation unique to naïve pluripotent stem cells, allowing near-perfect maintenance of proteome composition. Our work unravels the mechanisms protecting the integrity of mammalian proteomes upon variations in protein synthesis rates.