Circadian rhythms in mRNA translation through activity require rhythms in levels.
GCN2 activity is influenced by uncharged tRNA levels, which activate the kinase to phosphorylate eIF2α during nutrient starvation.
The circadian clock regulates the interaction of CPC-3 and with ribosomes, essential for maintaining CPC-3 activity rhythms.
A temperature-sensitive mutant with high uncharged tRNA levels disrupts rhythmic interactions and abolishes CPC-3 activity rhythms.
Disrupting the interaction between GCN1 and uncharged tRNA affects the rhythmic activity of CPC-3 in the absence of GCN20.
These findings suggest a mechanism linking circadian rhythms to the regulation of mRNA translation and cellular energy levels.
Simplified
Misregulation of the activity of GCN2, the kinase that phosphorylates and inactivates translation initiation factor eIF2α, has been implicated in several health disorders, underscoring the need to determine the mechanisms controlling GCN2 activation. During nutrient starvation, increased levels trigger and GCN20 proteins to mediate the binding of uncharged tRNA to GCN2 to activate the kinase to phosphorylate eIF2α. Under constant conditions, activation of thehomolog of GCN2, , is controlled by the circadian clock. However, how the circadian clock controls the rhythmic activity of CPC-3 was not known. We found that the clock regulates CPC-3 and GCN1 interaction with ribosomes and show that these interactions are necessary for clock regulation of CPC-3 activity. CPC-3 activity rhythms, and the rhythmic interaction of CPC-3 and GCN1 with ribosomes, are abolished in a temperature-sensitive valyl-tRNA synthetase mutant () that has high levels of uncharged tRNAat all times of the day. Disrupting the interaction between GCN1 and uncharged tRNA in the absence of GCN20 altered rhythmic CPC-3 activity, indicating that the clock controls the interaction between uncharged tRNA and GCN1. Together, these data support that circadian rhythms in mRNA translation through CPC-3 activity require rhythms in uncharged tRNA levels that drive the rhythmic interaction between CPC-3 and GCN1 with ribosomes. This regulation uncovers a fundamental mechanism to ensure temporal coordination between peak cellular energy levels and the energetically demanding process of mRNA translation. Neurospora crassa un-3ts Val
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