Minimal upstream open reading frame of Per2 mediates phase fitness of the circadian clock to day/night physiological body temperature rhythm
Minimal upstream open reading frame of Per2 mediates phase fitness of the circadian clock to day/night physiological body temperature rhythm
复制标题
Per2的最小上游开放阅读框介导生物钟对昼夜生理体温节律的相位适应性
DOI：
10.1016/j.celrep.2023.112157
复制
发表时间：
2023
期刊：
影响因子：
8.8
通讯作者：
Doi Masao
中科院分区：
文献类型：
--
作者：
Miyake Takahito;Inoue Yuichi;Shao Xinyan;Seta Takehito;Aoki Yuto;Nguyen Pham Khanh Tien;Shichino Yuichi;Sasaki Junko;Sasaki Takehiko;Ikawa Masahito;Yamaguchi Yoshiaki;Okamura Hitoshi;Iwasaki Shintaro;Doi Masao
恒温动物的体温不是恒定的，而是在一个生理范围内(例如，小鼠的35°C-38.5°C)表现出规律的昼夜波动，构成协调昼夜时钟调节的生理的基本系统信号。在这里，我们找到了由哺乳动物核心时钟基因Per2的5‘非编码区编码的最小上游开放阅读框架(UORF)，并揭示了它作为依赖温度的昼夜节律时钟夹带的调节模块的作用。生理范围内的温度变化不会影响转录，而是通过其最小的uORF增加Per2的翻译。位于温度依赖的PER2蛋白合成上游的Per2最小uORF的遗传消融和磷脂酰肌醇-3-激酶的抑制，扰乱了细胞对模拟体温周期的携带。在生物体水平上，Per2Minimum uORF突变皮肤显示伤口愈合延迟，表明uORF介导的PER2调节对最佳组织动态平衡至关重要。结合转录调控，Per2Minimum uORF介导的翻译可能增强昼夜生理学的适合性。
Body temperature in homeothermic animals does not remain constant but displays a regular circadian fluctuation within a physiological range (e.g., 35°C–38.5°C in mice), constituting a fundamental systemic signal to harmonize circadian clock-regulated physiology. Here, we find the minimal upstream open reading frame (uORF) encoded by the 5′ UTR of the mammalian core clock genePer2and reveal its role as a regulatory module for temperature-dependent circadian clock entrainment. A temperature shift within the physiological range does not affect transcription but instead increases translation ofPer2through its minimal uORF. Genetic ablation of thePer2minimal uORF and inhibition of phosphoinositide-3-kinase, lying upstream of temperature-dependent Per2 protein synthesis, perturb the entrainment of cells to simulated body temperature cycles. At the organismal level,Per2minimal uORF mutant skin shows delayed wound healing, indicating that uORF-mediated Per2 modulation is crucial for optimal tissue homeostasis. Combined with transcriptional regulation,Per2minimal uORF-mediated translation may enhance the fitness of circadian physiology.