Proceedings of the National Academy of Sciences of the United States of AmericaMay 2, 2020

Daily body clock control of eIF2α phosphorylation is needed for regular protein production cycles

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Updated Mar 19, 2026

Abstract

Inhibitory phosphorylation of eIF2α peaks during the subjective day, indicating a clock-controlled mechanism for regulating translation initiation.

Phosphorylation levels of eIF2α are regulated by the circadian clock.
The eIF2α kinase is rhythmically activated, which is essential for the cycling of P-eIF2α.
Alterations in charged tRNA levels disrupt the rhythmic activation of CPC-3.
In vitro studies show that clock-controlled P-eIF2α levels lead to reduced translation during the day.
In vivo, rhythmic P-eIF2α levels are necessary for the synthesis of specific proteins.
Loss of rhythmic P-eIF2α levels is associated with reduced linear growth rates in Neurospora crassa.

Simplified

The circadian clock in eukaryotes controls transcriptional and posttranscriptional events, including regulation of the levels and phosphorylation state of translation factors. However, the mechanisms underlying clock control of translation initiation, and the impact of this potential regulation on rhythmic protein synthesis, were not known. We show that inhibitory phosphorylation of eIF2α (P-eIF2α), a conserved translation initiation factor, is clock controlled in, peaking during the subjective day. Cycling P-eIF2α levels required rhythmic activation of the eIF2α kinase (the homolog of yeast and mammalian GCN2), and rhythmic activation of CPC-3 was abolished under conditions in which the levels of charged tRNAs were altered. Clock-controlled accumulation of P-eIF2α led to reduced translation during the day in vitro and was necessary for the rhythmic synthesis of select proteins in vivo. Finally, loss of rhythmic P-eIF2α levels led to reduced linear growth rates, supporting the idea that partitioning translation to specific times of day provides a growth advantage to the organism. Together, these results reveal a fundamental mechanism by which the clock regulates rhythmic protein production, and provide key insights into how rhythmic translation, cellular energy, stress, and nutrient metabolism are linked through the levels of charged versus uncharged tRNAs. Neurospora crassa

Key numbers

2×

Increase in P-eIF2α Levels

P-eIF2α levels were twofold higher in untreated WT cells at DD40 compared to DD28.

30%

Decrease in Growth Rate

Growth rate was reduced to a level comparable to Δ cells when P-eIF2α levels were disrupted.

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Funding

Competing interests

The authors declare no competing interest.

PubMed

Daily body clock control of eIF2α phosphorylation is needed for regular protein production cycles

Abstract

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Abstract

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Related papers

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