Ribosome biogenesis mediates the translational increase of nonoptimal codon transcripts during IFN-β stimulation

The interferon response is a signalling 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 is not fully understood. 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 abundance. Multi-omics analysis of RNA-seq and LC-MS/MS data reveal proteins, including several ISGs, that are translationally up-regulated in IFN-β-stimulated cells depleted of ribosome biogenesis factor BOP1. Analysis of codon usage demonstrates a significant reduction in codon optimality for proteins that are translationally up-regulated during BOP1 knockdown and IFN-β stimulation. Using reporter constructs, we demonstrate that codon nonoptimal reporters are translated more than codon-optimized reporters in BOP1-depleted IFN-β cells. We propose that ribosome biogenesis may in part regulate the translational fine-tuning of integral ISG protein production to ensure optimal interferon responses, with potential effects extending beyond this pathway.