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 the catabolism of aromatic amino acids simultaneously with the induction of the amino acid biosynthetic regulon driven by the integrated stress response factor GCN4. We further identified the translational control of Pho85 cyclin 5 (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 mechanisms controlling translation during environmental challenges. [Display omitted] •Yeast adapt to survive acute, dramatic depletion of cap-binding protein eIF4E•eIF4E depletion reduces the abundance and translation of short, stable mRNAs•Depleting eIF4E dysregulates expression of amino acid metabolic genes•Feedback regulator Pcl5 is controlled by upstream ORFs and an A27 tract in its 5′ UTR The cap-binding protein eIF4E protects mRNAs from degradation and promotes their translation. Although eIF4E is essential, Diamond et al. show that yeast survive and adapt after near total eIF4E depletion. Acute depletion of cap-binding protein reduces expression of short, highly expressed mRNAs at multiple levels and dysregulates amino acid metabolic genes.