Impact of protein degradation and cell growth on mammalian proteomes

Cellular protein concentrations are controlled by rates of synthesis and clearance, the lat-ter including protein degradation and dilution due to growth. Thus, cell growth rate may influence the mechanisms controlling variation in protein concentrations. To quantify this influence, we analyzed the growth-dependent effects of protein degradation within a cell type (between activated and resting human B-cells), across human cell types and mouse tissues. This analysis benefited from deep and accurate quantification of over 12,000 proteins across four primary tissues using plexDIA. The results indicate that growth-dependent dilution can account for 40 % of protein concentration changes across conditions. Furthermore, we find that the variation in protein degradation rates is sufficient to account for up to 50 % of the variation in concentrations within slowly growing cells as contrasted with 7 % in growing cells. Remarkably, degradation rates differ significantly between proteoforms encoded by the same gene and arising from alternative splicing or alternate RNA decoding. These proteoform-specific degradation rates substantially determine the proteoform abundance, especially in the brain. Thus, our model and data unify previous observations with our new results and demonstrate substantially larger than previously appreciated contributions of protein degradation to protein variation at slow growth, both across proteoforms and tissue types.