Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance.

Abstract

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.

• Authors: Jiajie Wei, Rigel J Kishton, Matthew Angel, Crystal S Conn, Nicole Dalla-Venezia, Virginie Marcel, Anne Vincent, Frédéric Catez, Sabrina Ferré, Lilia Ayadi, Virginie Marchand, Devin Dersh, James S Gibbs, Ivaylo P Ivanov, Nathan Fridlyand, Yohann Couté, Jean-Jacques Diaz, Shu-Bing Qian, Louis M Staudt, Nicholas P Restifo, Jonathan W Yewdell
• Journal: Molecular cell (Mol Cell) Vol. 73 Issue 6 Pg. 1162-1173.e5 (03 21 2019) ISSN: 1097-4164 [Electronic] United States
• PMID: 30712990 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• Histocompatibility Antigens Class I
• RPL28 protein, human
• RPS28 protein, human
• Ribosomal Proteins
• ribosomal protein L6

Topics

• Animals
• Antigen Presentation
• Cell Line, Tumor
• Coculture Techniques
• HEK293 Cells
• Histocompatibility Antigens Class I (biosynthesis, immunology)
• Host-Pathogen Interactions
• Humans
• Immunologic Surveillance
• Influenza A virus (immunology, pathogenicity)
• Melanoma (immunology, metabolism)
• Mice, Inbred C57BL
• Mice, Transgenic
• Ribosomal Proteins (genetics, metabolism)
• Ribosome Subunits, Large, Eukaryotic (genetics, metabolism)
• Ribosome Subunits, Small, Eukaryotic (genetics, metabolism)
• Skin Neoplasms (immunology, metabolism)
• T-Lymphocytes (immunology, metabolism, virology)