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.
Author Info: (1) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: weijiajie@gmail.com. (2) National Cancer
Author Info: (1) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: weijiajie@gmail.com. (2) National Cancer Institute, NIH, Bethesda, MD 20892, USA. (3) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. (4) Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA. (5) University of Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Center Leon Berard, Center de Recherche en Cancerologie de Lyon, Lyon, 69373 Cedex 08, France. (6) University of Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Center Leon Berard, Center de Recherche en Cancerologie de Lyon, Lyon, 69373 Cedex 08, France. (7) University of Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Center Leon Berard, Center de Recherche en Cancerologie de Lyon, Lyon, 69373 Cedex 08, France. (8) University of Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Center Leon Berard, Center de Recherche en Cancerologie de Lyon, Lyon, 69373 Cedex 08, France. (9) University of Grenoble Alpes, CEA, INSERM, BIG-BGE, 38000 Grenoble, France. (10) Next-Generation Sequencing Core Facility, UMS2008 IBSLor CNRS-INSERM-University of Lorraine, 54505 Vandoeuvre-les-Nancy, France; Laboratory IMoPA, UMR7365 CNRS-University of Lorraine, 54505 Vandoeuvre-les-Nancy, France. (11) Next-Generation Sequencing Core Facility, UMS2008 IBSLor CNRS-INSERM-University of Lorraine, 54505 Vandoeuvre-les-Nancy, France; Laboratory IMoPA, UMR7365 CNRS-University of Lorraine, 54505 Vandoeuvre-les-Nancy, France. (12) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. (13) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. (14) Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA. (15) Laboratory of Translational Biology, School of Biosciences and Biotechnology, University of Camerino, Camerino MC 62032, Italy. (16) University of Grenoble Alpes, CEA, INSERM, BIG-BGE, 38000 Grenoble, France. (17) University of Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Center Leon Berard, Center de Recherche en Cancerologie de Lyon, Lyon, 69373 Cedex 08, France. (18) Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA. (19) Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. (20) National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, Center for Cancer Research, NIH, Bethesda, MD 20892, USA. (21) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: jyewdell@niaid.nih.gov.
