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

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

Sun et al. studied how protein decay rates through dilution and active degradation adapt to changes in protein synthesis rates. A passive mechanism is sufficient to explain adaptation in most cell types, except for naive pluripotent stem cells that also leverage the mTOR pathway to achieve near-perfect adaptation.

Proteome-wide decay rates adapt to global changes in protein synthesis rate

A passive mechanism is sufficient to explain this adaptation in most cell types

An additional mTOR-driven mechanism allows for near-perfect adaptation in naive ES cells

Divergent adaptation of degradation and dilution rates leads to proteome imbalance

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

SUMMARY

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 mechanistic/mammalian target of rapamycin signaling. Passive adaptation hinges on changes in the production rate of the machinery governing protein decay and allows for partial maintenance of the cellular proteome. Sustained changes in mTOR signaling provide an additional layer of adaptation unique to naive pluripotent stem cells, allowing for near-perfect maintenance of proteome composition. Our work unravels the mechanisms protecting the integrity of mammalian proteomes upon variations in protein synthesis rates. A record of this paper's transparent peer review process is included in the supplemental information.