eIF1 modulates the recognition of sub-optimal translation start sites and steers gene expression control mediated by uORFs.

Alternative translation initiation mechanisms such as leaky scanning and re-initiation potentiate the polycistronic nature of transcripts. By allowing for reprogrammed translation, these mechanisms can mediate biological responses to stress stimuli. We combined proteomics with ribosome profiling and mRNA sequencing to identify the biological targets of translation control triggered by the eukaryotic translation initiation factor 1 (eIF1), a protein implicated in the stringency of start codon selection. We quantified expression changes of over 4,000 proteins and 10,000 actively translated transcripts, leading to the identification of 245 transcripts undergoing translational control mediated by upstream open reading frames (uORFs) upon eIF1 deprivation. The stringency of start codon selection and preference for an optimal nucleotide context were largely diminished leading to translational upregulation of uORFs with sub-optimal start sites. Affected genes were implicated in energy production and sensing of metabolic stress. Interestingly, knockdown of eIF1 elicited a synergic response from eIF5 and eIF1B.