eIF5A coordinates the transcription and translation of its target genes

Maintaining balanced cellular protein levels requires precise control of gene expression and effective coordination between the various stages of the process, from transcription to translation. In recent years, several components of the translation apparatus have been found in the nuclei of various eukaryotes, where they regulate transcription, mRNA processing or export, thereby integrating different stages of gene expression. eIF5A is an essential and evolutionarily conserved translation elongation factor that is involved in viral infection and in the development of diseases such as cancer and neurodevelopmental disorders. eIF5A promotes translation elongation by binding to ribosomes that stall at codons encoding problematic amino acids for peptide bond formation, such as consecutive prolines, also known as polyproline motifs. Although eIF5A shuttles between the nucleus and cytoplasm, its specific nuclear roles remain poorly defined. Here, we demonstrate that nuclear yeast eIF5A binds to chromatin and represses gene transcription by preventing the binding of RNA polymerase II. Importantly, chromatin binding and transcriptional repression by eIF5A have a higher impact on genes encoding its own translational targets. The presence of polyproline motifs in genes imposes both translation and transcriptional control by eIF5A. Furthermore, eIF5A’s active engagement in cytoplasmic translation is necessary for its role in repressing transcription. Our results suggest that eIF5A coordinates gene expression by promoting the cytoplasmic translation of specific genes while repressing their transcription in the nucleus, thus ensuring efficient final protein synthesis.