Using a lentiviral shRNA panel to knockdown (KD) each of the 80 ribosomal proteins (RPs), Wei et al. identified three RPs modulating MHCI-peptide levels independent of source protein and transcriptome-wide effects. In HEK293(MuH2-Kb) cells infected with a virus containing the SIINFEKL epitope, RPL28 KD enhanced SIINFEKL-Kb presentation. RPL6 KD did the opposite by inhibiting ubiquitin- and proteasome-dependent generation of rapidly degraded nascent polypeptides (DRiPs). RPS28 KD increased HLA-A2 levels by increasing non-canonical translation. Somatic mutations in ribosome subunits may thus affect immune surveillance.
Contributed by Alex Najibi
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.