Ribosome biogenesis mediates the translational increase of codon non-optimal transcripts during IFN stimulation

The interferon response is a signaling pathway unique to vertebrates that links the innate and adaptive immune responses. Interferons signal through a cascade of factors including the JAK-STAT pathway to induce the transcription of hundreds of interferon stimulated genes (ISGs). Although the main interferon signal transduction pathways and ISGs have been elucidated, translational regulation of ISG transcripts has not been fully investigated. Prior work demonstrated that ribosomal protein RPL28 negatively regulates a subset of ISGs; however, we find that this effect may be due to a reduction in overall ribosome availability. Multi-omics analysis of RNA-seq and LC-MS/MS data reveal proteins that are translationally up-regulated during BOP1 knockdown and IFN-β stimulation, including an enrichment of ISGs. Analysis of codon optimality demonstrates a significant reduction in codon optimality for proteins that are translationally up-regulated during BOP1 knockdown and IFN-β stimulation. Extremely codon-optimized and -non-optimized reporter constructs were tested under these conditions and demonstrate that BOP1 knockdown increases translation of the non-optimal reporter during IFN stimulation. We propose that this is a form of translational fine-tuning of the IFN in order to ensure the production of integral proteins during times of cellular stress when translation machinery may be inhibited.