Costanzo Kara M, Prifti Matthew V, Todi Sokol V, Mohan Ryan D
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United States.
Department of Neurology, Wayne State University School of Medicine, Detroit, MI, United States.
Front Neurosci. 2025 Aug 26;19:1632905. doi: 10.3389/fnins.2025.1632905. eCollection 2025.
To align sleep-wake behavior and internal physiology with the Earth's 24-h light-dark cycle, organisms rely on circadian clocks-endogenous timekeeping systems that anticipate and adapt to daily environmental changes. These clocks are governed by transcription-translation feedback loops that produce rhythmic oscillations in gene expression, including key regulators such as PERIOD and CRYPTOCHROME. The timing and stability of these proteins are tightly controlled by post-translational mechanisms, including ubiquitin-mediated degradation. The ubiquitin-proteasome system (UPS) ensures that clock proteins are cleared at precise times within the circadian cycle, a process which is essential for resetting the molecular clock and sustaining robust circadian rhythms. Disruption of this process can have profound impacts on human health and contribute to impairments in sleep timing, circadian phase, and rhythm amplitude. In this review, we focus on the mechanistic role of the UPS in circadian clock regulation, summarize key E3 ligases and deubiquitinating enzymes implicated in clock protein turnover, and highlight the essential role of the UPS on sleep timing and overall circadian biological homeostasis.
为了使睡眠-觉醒行为和内部生理机能与地球24小时的昼夜循环保持一致，生物体依赖昼夜节律时钟——一种内源性计时系统，该系统能够预测并适应日常环境变化。这些时钟受转录-翻译反馈回路调控，该回路在基因表达中产生节律性振荡，包括关键调节因子，如周期蛋白（PERIOD）和隐花色素（CRYPTOCHROME）。这些蛋白质的定时和稳定性受到翻译后机制的严格控制，包括泛素介导的降解。泛素-蛋白酶体系统（UPS）确保时钟蛋白在昼夜节律周期内的精确时间被清除，这一过程对于重置分子时钟和维持稳健的昼夜节律至关重要。这一过程的破坏会对人类健康产生深远影响，并导致睡眠时间、昼夜节律相位和节律幅度受损。在本综述中，我们重点关注UPS在昼夜节律时钟调节中的机制作用，总结参与时钟蛋白周转的关键E3连接酶和去泛素化酶，并强调UPS对睡眠时间和整体昼夜生物稳态的重要作用。
