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

Salil Saurav Pathak, Dong Liu, Tianbao Li, Nuria de Zavalia, Lei Zhu, Jin Li, Ramanujam Karthikeyan, Tommy Alain, Andrew C. Liu, Kai Florian Storch, Randal J. Kaufman, Victor X. Jin, Shimon Amir, Nahum Sonenberg, Ruifeng Cao

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)724-735.e6
JournalNeuron
Volume104
Issue number4
DOIs
StatePublished - Nov 20 2019

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

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