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

<p><span>Protein synthesis is </span><span>metabolically costly </span><span>and</span><span> must be tightly coordinated with </span><span>changing </span><span>cellular needs and nutrient availability. T</span><span>he cap-binding protein eIF4E</span><span> makes </span><span>the earliest contact between mRNAs and the translation machinery</span><span>, offering a key regulatory nexus</span><span>. </span><span>W</span><span>e acute</span><span>ly</span><span> deplet</span><span>ed</span> <span>this essential protein </span><span>and </span><span>found </span><span>s</span><span>urprisingly modest effects on cell growth and </span><span>recovery of </span><span>protein synthesis.</span><span> Paradoxically, </span><span>impaired protein biosynthesis upregulated </span><span>genes involved in catabolism of aromatic amino acids</span><span>simultaneously with the </span><span>induction of the </span><span>amino acid</span><span> biosynthetic regulon</span> <span>driven</span> <span>by </span><span>the integrated stress response factor</span> <span>GCN4</span><span>. </span><span>W</span><span>e</span><span> further</span><span> identified translation</span><span>al </span><span>control</span><span> of </span><span>PCL5</span><span>, </span><span>a negative regulator of Gcn4, that provides a consistent protein-to-mRNA ratio under varied translation environments. </span><span>This</span> <span>regulation </span><span>depende</span><span>d in part</span><span> on a uniquely long poly-(A) tract in the </span><span>PCL5</span><span> 5&acute; UTR and poly-(A) binding protein. Collectively, these results highlight</span> <span>how eIF4E connects</span> <span>protein synthesis </span><span>to</span> <span>metabolic gene regulation</span><span>,</span><span>uncover</span><span>ing</span><span> new mechanisms control</span><span>ling</span> <span>translation</span><span> during environmental challenges.</span></p>