Abstract
ABSTRACTAlthough costly to maintain, protein homeostasis is indispensable for normal cellular function and long-term health. In mammalian cells and tissues, daily variation in global protein synthesis has been observed, but its utility and consequences for proteome integrity are not fully understood. Using several different protein labelling strategies, we show that protein degradation varies in-phase with protein synthesis, facilitating rhythms in turnover rather than abundance. This results in daily consolidation of proteome renewal whilst minimising changes in composition. By combining mass spectrometry with pulsed isotopic labelling of nascently synthesised proteins, we gain direct insight into the relationship between protein synthesis and abundance proteome-wide, revealing that coupled rhythms in synthesis and turnover are especially salient to the assembly of macromolecular protein complexes, such as ribosomes, RNA polymerase, and chaperonin complex. Daily turnover and proteasomal degradation rhythms render cells and mice more sensitive to proteotoxic stress at specific times of day, potentially contributing to daily rhythms in the efficacy of proteasomal inhibitors against cancer. Our findings suggest that circadian rhythms function to minimise the bioenergetic cost of protein homeostasis through temporal consolidation of turnover.
Publisher
Cold Spring Harbor Laboratory
Cited by
4 articles.
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