Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance

The MHC class I antigen presentation system enables T cell immunosurveillance of cancers and viruses. A substantial fraction of the immunopeptidome derives from rapidly degraded nascent polypeptides (DRiPs). By knocking down each of the 80 ribosomal proteins, we identified proteins that modulate peptide generation without altering source protein expression. We show that 60S ribosomal proteins L6 (RPL6) and RPL28, which are adjacent on the ribosome, play opposite roles in generating an influenza A virus-encoded peptide. Depleting RPL6 decreases ubiquitin-dependent peptide presentation, whereas depleting RPL28 increases ubiquitin-dependent and -independent peptide presentation. 40S ribosomal protein S28 (RPS28) knockdown increases total peptide supply in uninfected cells by increasing DRiP synthesis from non-canonical translation of “untranslated” regions and non-AUG start codons and sensitizes tumor cells for T cell targeting. Our findings raise the possibility of modulating immunosurveillance by pharmaceutical targeting ribosomes. [Display omitted] •Ribosome heterogeneity controls MHC class I peptide ligand presentation•RPL6 and RPL28 play opposing roles in viral peptide generation•RPS28 controls MHC class I peptide generation by modulating non-canonical translation•Ribosomal proteins influence CD8+ T cell cancer immunosurveillance Wei et al. show that cells with ribosomes lacking any one of three ribosomal protein subunits have an altered capacity to generate MHC class I peptides for immunosurveillance and that tumor cells can potentially use this mechanism to avoid CD8 T cell immunosurveillance.