Wake-sleep cycles are severely disrupted by diseases affecting cytoplasmic homeostasis.
Wake-sleep cycles are severely disrupted by diseases affecting cytoplasmic homeostasis.
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DOI：
10.1073/pnas.2003524117
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发表时间：
2020-11-10
影响因子：
11.1
通讯作者：
Lee C
中科院分区：
文献类型：
--
作者：
Beesley S;Kim DW;D'Alessandro M;Jin Y;Lee K;Joo H;Young Y;Tomko RJ Jr;Faulkner J;Gamsby J;Kim JK;Lee C
包括觉醒-睡眠周期在内的昼夜节律是由自我维持的转录负反馈环产生的分子时间线索驱动的。在所有时钟蛋白中，Period(PER)被认为是起搏器蛋白，因为它的积累和核进入的节奏产生了反馈抑制的时间和持续时间。在这里，我们对PER节律是如何产生的提供了一个新的理解：PER分子相互作用的集体作用，而不是单个分子的随机质量作用，允许补偿单个分子的空间和时间差异(或“噪声”)。我们还表明，集体每节律需要健康的细胞质运输，昼夜睡眠障碍可能出现在肥胖、衰老和神经退行性疾病等细胞质充血的情况下。生物钟是以转录反馈环为基础的，在反馈抑制之前有一个基本的时间延迟。以前的工作表明，周期(PER)蛋白通过抑制复合体的节律性核积累以及随后与反馈环中的激活复合体的相互作用来产生昼夜节律信号。尽管反馈抑制的这种时间表现是PER在核进入前的细胞质运输的直接结果，但起搏器的这种空间调节如何影响昼夜节律在很大程度上还没有被探索。在这里，我们表明，如果细胞质运输被任何导致细胞质充血增加的疾病扰乱，昼夜节律，包括觉醒-睡眠周期，都会延长和严重不稳定。此外，我们还发现，生物钟中的时延和稳健性是由PER分子的延迟和集体磷酸化以及随后的同步核进入无缝产生的。这些结果提供了清晰的机制洞察为什么昼夜节律和睡眠障碍会出现在代谢和神经退行性疾病以及衰老等临床条件下，在这些疾病中，细胞质充血。
Circadian rhythms including wake-sleep cycles are driven by molecular time cues generated by a self-sustaining transcriptional negative feedback loop. Among all clock proteins, PERIOD (PER) is considered the pacemaker protein because its rhythm of accumulation and nuclear entry generates the timing and duration of feedback inhibition. Here we provide a new understanding of how robust PER rhythms are generated: the collective action of interacting PER molecules, not a random mass action of individual molecules, allows compensation of spatial and temporal differences (or “noise”) of individual molecules. We also show that the collective PER rhythm requires healthy cytoplasmic trafficking, and that circadian sleep disorders can arise in such conditions as obesity, aging, and neurodegenerative disorders in which the cytoplasm becomes congested. The circadian clock is based on a transcriptional feedback loop with an essential time delay before feedback inhibition. Previous work has shown that PERIOD (PER) proteins generate circadian time cues through rhythmic nuclear accumulation of the inhibitor complex and subsequent interaction with the activator complex in the feedback loop. Although this temporal manifestation of the feedback inhibition is the direct consequence of PER’s cytoplasmic trafficking before nuclear entry, how this spatial regulation of the pacemaker affects circadian timing has been largely unexplored. Here we show that circadian rhythms, including wake-sleep cycles, are lengthened and severely unstable if the cytoplasmic trafficking of PER is disrupted by any disease condition that leads to increased congestion in the cytoplasm. Furthermore, we found that the time delay and robustness in the circadian clock are seamlessly generated by delayed and collective phosphorylation of PER molecules, followed by synchronous nuclear entry. These results provide clear mechanistic insight into why circadian and sleep disorders arise in such clinical conditions as metabolic and neurodegenerative diseases and aging, in which the cytoplasm is congested.
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影响因子：
9.8
作者：
Hennig S;Strauss HM;Vanselow K;Yildiz O;Schulze S;Arens J;Kramer A;Wolf E
通讯作者：
Wolf E
影响因子：
64.5
作者：
Chiu JC;Ko HW;Edery I
通讯作者：
Edery I
DOI：
10.1016/j.cub.2013.08.005
发表时间：
2013-10-21
期刊：
Current biology : CB
影响因子：
--
作者：
Chen R;D'Alessandro M;Lee C
通讯作者：
Lee C
影响因子：
64.8
作者：
HARDIN, PE;HALL, JC;ROSBASH, M
通讯作者：
ROSBASH, M
影响因子：
1.1
作者：
Kim YH;Han ME;Oh SO
通讯作者：
Oh SO