Depletion of cap-binding protein eIF4E dysregulates amino acid metabolic gene expression

Protein synthesis is metabolically costly and must be tightly coordinated with changing cellular needs and nutrient availability. The cap-binding protein eIF4E makes the earliest contact between mRNAs and the translation machinery, offering a key regulatory nexus. We acutely depleted this essential protein and found surprisingly modest effects on cell growth and recovery of protein synthesis. Paradoxically, impaired protein biosynthesis upregulated genes involved in catabolism of aromatic amino acidssimultaneously with the induction of the amino acid biosynthetic regulon driven by the integrated stress response factor GCN4. We further identified translational control of PCL5, a negative regulator of Gcn4, that provides a consistent protein-to-mRNA ratio under varied translation environments. This regulation depended in part on a uniquely long poly-(A) tract in the PCL5 5´ UTR and poly-(A) binding protein. Collectively, these results highlight how eIF4E connects protein synthesis to metabolic gene regulation,uncovering new mechanisms controlling translation during environmental challenges.