Oxygen level regulates N-terminal translation elongation of selected proteins through deoxyhypusine hydroxylation

Hypusine is a post-translational modification on eukaryotic translation initiation factor 5A (eIF5A). The last step of hypusine biosynthesis, deoxyhypusine hydroxylation, is an oxygen-dependent reaction. Here we show that deletion of the deoxyhypusine hydroxylase Lia1 compromises yeast respiration through translation downregulation of selected proteins in the respiration pathway. The translation suppression, because of the lack of deoxyhypusine hydroxylation, mainly affects translation of the N termini of the proteins, independent of the presence of proline residues but likely dependent on the interaction between the N-terminal nascent peptide and the ribosomal peptide exit tunnel. Proteomics and biochemical studies reveal that Lia1 deletion decreases N-terminal translation of proteins involved in mitochondrial respiration, oxidative stress response, and protein folding. Our work uncovers functions of the hypusine modification by considering the substrate requirement of the post-translational modification, highlights the unique challenges of translating the N termini of proteins, and reveals an oxygen-sensing mechanism in eukaryotic cells.