Summary: Stress makes the circadian clock tick faster and better.
Source: University of Minnesota Medical School
The human body has an internal biological clock that is constantly running. Our well-being is dependent on the function of that clock. New research from the University of Minnesota Medical School found a little stress can make the circadian clock run better and faster.
Research in the past several decades has found that our body has evolved a set of machinery, called the circadian clock, that internally drives rhythms in almost every cell. The activities of the circadian clock are influenced by various signals in the cells.
In a recent study published in Neuron, Ruifeng Cao, MD, PhD, Assistant Professor in the Department of Biomedical Sciences at the Medical School, and a team of seven laboratories in the U.S. and Canada focused on the crosstalk between cellular stress signals and the circadian clock.
Cells respond to various stress signals by activating a signal transduction cascade that is centered on the protein eIF2α, which is a pivotal factor that orchestrates protein synthesis in cells. Cao and his team found that in one’s central brain clock, stress leads to rhythmic phosphorylation of eIF2α, which promotes production of the ATF4 protein. The ATF4 protein activates the Per2 gene, which ultimately makes the clock tick faster. They concluded that this mechanism is necessary to maintain a robust clock, and therefore, that stress signals influence the speed and robustness of the circadian clock.
It has been known that the circadian clock gets broken in many diseases, but the reason for it has been unclear. Cao’s finding may provide insight into this unanswered question, as it is the first connection between two fundamental processes in cells: stress response and circadian timekeeping. One explanation could be that stress responses frequently go awry in diseased conditions, which may, in turn, mess up the clock.
“The next step is a more thorough and larger-scale study on the crosstalk between the cellular stress network and the circadian clock,” said Cao. “Hopefully our work can lead to discovering medicine that can manage the stress level and regulate the clock function in disease to keep people healthier.”
Source:
University of Minnesota Medical School
Media Contacts:
Kelly Glynn – University of Minnesota Medical School
Image Source:
The image is adapted from the University of Minnesota Medical School news release.
Original Research: Closed access
“The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4”. Ruifeng Cao et al.
Neuron doi:10.1016/j.neuron.2019.08.007.
Abstract
The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4
Highlights
• GCN2 rhythmically phosphorylates eIF2α in the suprachiasmatic circadian clock
• eIF2α phosphorylation bidirectionally controls circadian period in cells and mice
• eIF2α phosphorylation promotes mRNA translation of Atf4
• ATF4 binds to the Per2 promoter region and activates its transcription
Summary
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.
