Summary: Small amounts of stress can sharpen and accelerate the body’s circadian clock.
Source: University of Minnesota Medical School
The human body runs on an internal biological clock that governs daily rhythms across virtually every cell. New research from the University of Minnesota Medical School shows that certain cellular stress signals can improve the speed and robustness of that circadian timing system.
Over recent decades, scientists have mapped the molecular machinery that produces circadian rhythms — an internal clockwork that helps coordinate sleep-wake cycles, metabolism, hormone release, and many other physiological processes. Those clock mechanisms are sensitive to a wide range of internal signals, and the new study explores how cellular stress pathways communicate with the clock to shape its timing.
Published in Neuron, the study was led by Ruifeng Cao, MD, PhD, Assistant Professor in the Department of Biomedical Sciences at the University of Minnesota Medical School, and involved a collaborative effort across seven laboratories in the United States and Canada. The team investigated how the integrated stress response interacts with the central brain clock located in the suprachiasmatic nucleus.
Cells encountering stressors activate a conserved signaling cascade centered on phosphorylation of the translation initiation factor eIF2α. This modification globally alters protein synthesis as part of the integrated stress response. The researchers discovered that, in the brain’s central clock, eIF2α phosphorylation occurs in a rhythmic pattern. That rhythmic phosphorylation enhances translation of the transcription factor ATF4, which in turn directly activates transcription of the Per2 gene — a core component of the molecular circadian machinery. The net effect is a faster, more robust clock cycle.
The work provides a clear mechanistic link between cellular stress signaling and circadian timing. Specifically, the eIF2α kinase GCN2 rhythmically phosphorylates eIF2α within the suprachiasmatic circadian clock. When eIF2α phosphorylation is increased, the circadian period shortens in both cultured fibroblasts and in live mice. Conversely, lowering eIF2α phosphorylation lengthens the period and weakens rhythmicity in animals. Mechanistically, phosphorylation of eIF2α promotes translation of Atf4 mRNA into ATF4 protein. The study identifies ATF4 binding motifs in multiple clock genes — including Per2, Per3, Cry1, Cry2, and Clock — and shows that ATF4 binds the TTGCAGCA motif in the Per2 promoter to activate its transcription.
These results suggest the integrated stress response (ISR) plays a significant role in maintaining precise circadian timing. Because circadian disruption is a common feature of many neurological and systemic diseases, the discovery that stress-response pathways directly modulate clock gene expression offers a plausible explanation for why the clock becomes dysregulated in illness: malfunctioning stress responses may distort the timing signals that keep the clock running smoothly.
“The next step is a more thorough and larger-scale study on the crosstalk between the cellular stress network and the circadian clock,” said Dr. Cao. “Hopefully our work can lead to discovering medicines that manage stress levels and restore clock function in disease, helping to preserve health.”
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
Title: “The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4”. Ruifeng Cao et al.
Journal: 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 by diverse stress stimuli to help neurons maintain homeostasis, with phosphorylation of eIF2α at the core of this adaptive process. This study reports a critical role for ISR in regulating the mammalian circadian clock. GCN2-dependent, rhythmic phosphorylation of eIF2α was observed in the suprachiasmatic nucleus. Experimentally increasing eIF2α phosphorylation shortened the circadian period in both fibroblasts and mice; reducing phosphorylation lengthened the period and impaired rhythmicity in animals. Mechanistically, phosphorylated eIF2α enhances translation of Atf4 mRNA. ATF4 recognition motifs are present in multiple clock genes, and ATF4 directly activates Per2 transcription by binding a specific promoter motif. Together, these findings establish an important role for ISR in circadian physiology and suggest a potential link between disrupted stress signaling and circadian dysfunction in brain disorders.