Ribosome biogenesis mediates the translational increase of non-optimal codon 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 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 availability. 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 biogeneis 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 non-optimal reporters are translated more than codon-optimized reporters in BOP1-depleted IFN-β cells. We propose that ribosome biogenesis regulates translational fine-tuning of integral protein production to ensure optimal interferon responses.