Other
15 Authors
- Liu D,
- Li T,
- Zhu L,
- Jin VX,
- Amir S,
- Sonenberg N,
- Cao R,
- Karthikeyan R,
- Alain T,
- Li J,
- Liu AC,
- Pathak SS,
- Storch KF,
- Kaufman RJ,
- de Zavalia N
| First Author | Pathak SS | Year | 2019 |
| Journal | Neuron | Volume | 104 |
| Issue | 4 | Pages | 724-735.e6 |
| PubMed ID | 31522764 | Mgi Jnum | J:282578 |
| Mgi Id | MGI:6381784 | Doi | 10.1016/j.neuron.2019.08.007 |
| Citation | Pathak SS, et al. (2019) The eIF2alpha Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4. Neuron 104(4):724-735.e6 |
| abstractText | 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 (eIF2alpha). Here, we report a critical role for ISR in regulating the mammalian circadian clock. The eIF2alpha kinase GCN2 rhythmically phosphorylates eIF2alpha in the suprachiasmatic circadian clock. Increased eIF2alpha phosphorylation shortens the circadian period in both fibroblasts and mice, whereas reduced eIF2alpha phosphorylation lengthens the circadian period and impairs circadian rhythmicity in animals. Mechanistically, phosphorylation of eIF2alpha 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. |
