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.
Bibliographical noteFunding Information:
We are grateful to David Ron at University of Cambridge for providing the Gcn2 −/− 129SvEv mice and Tim M. Townes at the University of Alabama at Birmingham for providing the Atf4 +/− mice. We thank Andrew Chapman and Isaac Edery for critical reading of the manuscript. This study was supported by a Faculty Start-Up Grant from the University of Minnesota Medical School and a grant from Whiteside Institute for Clinical Research to R.C., a grant from the Canadian Institutes of Health Research (CIHR) to N.S. ( MOP7214 ), a grant from CIHR to S.A. ( MOP142458 ), grants from National Institute of Health (NIH R01 DK113171 , R01 CA198103 , and R24 DK110973 ) to R.J.K., and grants from NIH ( R01 GM114142 and U54 CA217297 ) to V.X.J.
© 2019 Elsevier Inc.
- circadian clock