Protein degradation and growth dependent dilution substantially shape mammalian proteomes

Abstract

Cellular protein abundances are controlled by rates of synthesis and clearance. Since the latter includes protein degradation and dilution due to cell growth, the growth rate may influence the mechanisms controlling variation in protein abundances. 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 all four primary tissues using plexDIA. The results indicate that growth-dependent dilution accounts for 40 % of protein abundance changes across conditions. Furthermore, the variation in protein clearance rates is sufficient to explain up to 50 % of the protein abundance differences within slowly growing cells as contrasted with 7 % in growing cells. Remarkably, clearance rates also regulate the abundance differences of proteoforms encoded by the same gene, such those arising from alternative splicing or alternate RNA decoding. Overall, our results demonstrate substantially larger than previously appreciated contributions of protein degradation to protein variation at slow growth, both across proteoforms and tissue types.