Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• The Major Histocompatibility Complex (MHC) class I pathway is crucial for T-cell immunosurveillance against pathogens and tumors.
• A significant portion of the peptides presented by MHC class I molecules originates from rapidly degraded nascent polypeptides (DRiPs).

Purpose of the Study:

• To identify ribosomal proteins that regulate peptide generation for T-cell immunosurveillance without affecting overall protein expression.
• To investigate the specific roles of ribosomal proteins RPL6, RPL28, and RPS28 in antigen presentation.

Main Methods:

• Systematic knockdown of each of the 80 ribosomal proteins.
• Analysis of peptide generation and presentation using influenza A virus-encoded peptides.
• Assessment of ubiquitin-dependent and -independent peptide presentation pathways.
• Evaluation of DRiP synthesis through non-canonical translation.

Main Results:

• Ribosomal proteins RPL6 and RPL28 exhibit opposing effects on the generation of an influenza A virus-encoded peptide.
• RPL6 depletion reduces ubiquitin-dependent peptide presentation.
• RPL28 depletion enhances both ubiquitin-dependent and -independent peptide presentation.
• RPS28 knockdown increases total peptide supply by enhancing DRiP synthesis via non-canonical translation, sensitizing tumor cells for T-cell targeting.

Conclusions:

• Specific ribosomal proteins play critical roles in modulating the immunopeptidome.
• Targeting ribosomal proteins offers a potential strategy for enhancing cancer immunosurveillance.
• Pharmaceutical targeting of ribosomes could be a novel approach to modulate immune surveillance.