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Neuron. 2019 Aug 26. pii: S0896-6273(19)30691-9. doi: 10.1016/j.neuron.2019.08.007. [Epub ahead of print]

The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4.

Author information

1
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA.
2
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
3
Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC H4B 1R6, Canada.
4
Douglas Mental Health University Institute and Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada.
5
Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
6
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
7
Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92307, USA.
8
Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC H4B 1R6, Canada. Electronic address: shimon.amir@concordia.ca.
9
Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada. Electronic address: nahum.sonenberg@mcgill.ca.
10
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA; Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA. Electronic address: rcao@umn.edu.

Abstract

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.

KEYWORDS:

ATF4; GCN2; Per2; SCN; circadian clock; eIF2; mouse

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