The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4
The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4
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DOI：
10.1016/j.neuron.2019.08.007
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发表时间：
2019-11-20
期刊：
影响因子：
16.2
通讯作者：
Cao, Ruifeng
中科院分区：
文献类型：
--
作者：
Pathak, Salil Saurav;Liu, Dong;Cao, Ruifeng
整合应激反应（ISR）是神经元对各种应激刺激的反应，以维持神经元的稳态。该过程的核心是真核翻译起始因子2 α（eIF2 α）的磷酸化。在这里，我们报告了ISR在调节哺乳动物生物钟中的关键作用。eIF2 α激酶GCN 2在视交叉上生物钟中有节奏地磷酸化eIF2 α。eIF2 α磷酸化增加缩短了成纤维细胞和小鼠的昼夜节律周期，而eIF2 α磷酸化减少延长了动物的昼夜节律周期并损害了昼夜节律性。在机制上，eIF2 α的磷酸化促进Atf4的mRNA翻译。ATF4结合基序在多个时钟基因中被鉴定，包括Per2、Per3、Cry1、Cry2和Clock。ATF4与Per2启动子中的TTGCAGCA基序结合并激活其转录。总之，这些结果证明了ISR在昼夜生理学中的重要作用，并提供了ISR失调和脑疾病昼夜功能障碍之间的潜在联系。
The integrated stress response (ISR) is activated in response to diverse stress stimuli to maintain homeostasis in neurons. Central to this process is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2 alpha). Here, we report a critical role for ISR in regulating the mammalian circadian clock. The eIF2 alpha kinase GCN2 rhythmically phosphorylates eIF2 alpha in the suprachiasmatic circadian clock. Increased eIF2 alpha phosphorylation shortens the circadian period in both fibroblasts and mice, whereas reduced eIF2 alpha phosphorylation lengthens the circadian period and impairs circadian rhythmicity in animals. Mechanistically, phosphorylation of eIF2 alpha promotes mRNA translation of Atf4. ATF4 binding motifs are identified in multiple clock genes, including Per2, Per3, Cry1, Cry2, and Clock. ATF4 binds to the TTGCAGCA motif in the Per2 promoter and activates its transcription. Together, these results demonstrate a significant role for ISR in circadian physiology and provide a potential link between dysregulated ISR and circadian dysfunction in brain diseases.