The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4.
|Title||The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Pathak SSaurav, Liu D, Li T, de Zavalia N, Zhu L, Li J, Karthikeyan R, Alain T, Liu AC, Storch K-F, Kaufman RJ, Jin VX, Amir S, Sonenberg N, Cao R|
|Date Published||2019 Aug 26|
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 (eIF2α). Here, we report a critical role for ISR in regulating the mammalian circadian clock. The eIF2α kinase GCN2 rhythmically phosphorylates eIF2α in the suprachiasmatic circadian clock. Increased eIF2α phosphorylation shortens the circadian period in both fibroblasts and mice, whereas reduced eIF2α phosphorylation lengthens the circadian period and impairs circadian rhythmicity in animals. Mechanistically, phosphorylation of eIF2α 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.
|Grant List||R01 GM114142 / GM / NIGMS NIH HHS / United States |
R24 DK110973 / DK / NIDDK NIH HHS / United States
U54 CA217297 / CA / NCI NIH HHS / United States