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

被引：53

作者：

Pathak, Salil Saurav ^{[1
]}

Liu, Dong ^{[1
]}

Li, Tianbao ^{[2
]}

de Zavalia, Nuria ^{[3
]}

Zhu, Lei ^{[4
]}

Li, Jin ^{[1
]}

Karthikeyan, Ramanujam ^{[1
]}

Alain, Tommy ^{[5
]}

Liu, Andrew C. ^{[6
]}

Storch, Kai-Florian ^{[4
]}

Kaufman, Randal J. ^{[7
]}

Jin, Victor X. ^{[2
]}

Amir, Shimon ^{[3
]}

Sonenberg, Nahum ^{[8
,9
]}

Cao, Ruifeng ^{[1
,10
]}

机构：

[1] Univ Minnesota, Dept Biomed Sci, Sch Med, Duluth, MN 55812 USA

[2] Univ Texas San Antonio, Dept Mol Med, Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA

[3] Concordia Univ, Ctr Studies Behav Neurobiol, Montreal, PQ H4B 1R6, Canada

[4] McGill Univ, Douglas Mental Hlth Univ, Inst & Dept Psychiat, Verdun, PQ H4H 1R3, Canada

[5] Univ Ottawa, Childrens Hosp, Dept Biochem Microbiol & Immunol, Eastern Ontario Res Inst, Ottawa, ON, Canada

[6] Univ Florida, Dept Physiol & Funct Genom, Coll Med, Gainesville, FL 32610 USA

[7] Sanford Burnham Prebys Med Discovery Inst, Degenerat Dis Program, La Jolla, CA 92307 USA

[8] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada

[9] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada

[10] Univ Minnesota, Dept Neurosci, Sch Med, Minneapolis, MN 55455 USA

来源：

NEURON | 2019年 / 104卷 / 04期

基金：

加拿大健康研究院;

关键词：

UNFOLDED PROTEIN RESPONSE; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; GENE-EXPRESSION; SUPRACHIASMATIC NUCLEUS; ER-STRESS; LIGHT; PHOSPHORYLATION; ENTRAINMENT; SLEEP;

D O I：

10.1016/j.neuron.2019.08.007

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 (eIF2 alpha). Here, we report a critical role for ISR in regulating the mammalian circadian clock. The eIF2 alpha kinase GCN2 rhythmically phosphorylates eIF2 alpha in the suprachiasmatic circadian clock. Increased eIF2 alpha phosphorylation shortens the circadian period in both fibroblasts and mice, whereas reduced eIF2 alpha phosphorylation lengthens the circadian period and impairs circadian rhythmicity in animals. Mechanistically, phosphorylation of eIF2 alpha 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.

引用

页码：724 / +

页数：18