MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Department of Medicine, University of Cambridge, Cambridge, UK.
EMBO J. 2024 Jul;43(13):2813-2833. doi: 10.1038/s44318-024-00121-5. Epub 2024 May 22.
Although 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 pulse-labelling strategies, here we gain direct insight into the relationship between protein synthesis and abundance proteome-wide. 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. Coupled rhythms in synthesis and turnover are especially salient to the assembly of macromolecular protein complexes, particularly the ribosome, the most abundant species of complex in the cell. 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 protein turnover.
尽管维持蛋白质平衡的成本高昂，但它对于细胞的正常功能和长期健康是不可或缺的。在哺乳动物细胞和组织中，已经观察到了全球蛋白质合成的日常变化，但它的用途及其对蛋白质组完整性的影响尚未完全了解。在这里，我们使用了几种不同的脉冲标记策略，直接深入了解了蛋白质合成与蛋白质组丰度之间的关系。我们表明，蛋白质降解与蛋白质合成呈同相变化，有利于周转率的节律变化，而不是丰度的变化。这导致了蛋白质更新的日常整合，同时最大限度地减少了组成的变化。合成和周转率的偶联节律对大分子蛋白质复合物的组装尤其重要，特别是核糖体，它是细胞中最丰富的复合物种类。每日的周转率和蛋白酶体降解节律使细胞和小鼠在一天中的特定时间对蛋白毒性应激更加敏感，这可能导致蛋白酶体抑制剂对癌症疗效的每日节律变化。我们的研究结果表明，昼夜节律通过蛋白质周转率的时间整合来最小化蛋白质平衡的生物能量成本。
