Circadian clock control of eIF2α phosphorylation is necessary for rhythmic translation initiation
| Autor: | Cheng Wu, Zhaolan Ding, Shanta Karki, Matthew S. Sachs, Olivia Kerr, Kathrina Castillo, Teresa M. Lamb, Deborah Bell-Pedersen |
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| Rok vydání: | 2020 |
| Předmět: |
Circadian clock
Eukaryotic Initiation Factor-2 cpc-3 eIF2α Biology Inhibitory postsynaptic potential translation initiation Neurospora crassa Fungal Proteins eIF-2 Kinase Eukaryotic translation Circadian Clocks Gene Expression Regulation Fungal circadian clock Protein biosynthesis Genetics Animals Phosphorylation Multidisciplinary Translation (biology) Metabolism Biological Sciences biology.organism_classification Cell biology Circadian Rhythm Protein Kinases Protein Processing Post-Translational |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance Circadian clock control of mRNA translation, which contributes to the daily cycling of at least 50% of the proteins synthesized in eukaryotic cells, is understudied. We show that the circadian clock in the model fungus Neurospora crassa regulates rhythms in phosphorylation and activity of the conserved translation initiation factor eIF2α, with a peak in phosphorylated eIF2α levels during the daytime. This leads to reduced mRNA translation of select messages during the day and increased translation at night. We demonstrate that rhythmic accumulation of phosphorylated eIF2α requires increased uncharged tRNA levels during the day to activate the eIF2α kinase, coordinating rhythmic translation initiation and protein production with nutrient and energy metabolism. 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 Neurospora crassa, peaking during the subjective day. Cycling P-eIF2α levels required rhythmic activation of the eIF2α kinase CPC-3 (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. |
| Databáze: | OpenAIRE |
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