Distinct pathways generate peptides from defective ribosomal products for CD8+ T cell immunosurveillance.

TitleDistinct pathways generate peptides from defective ribosomal products for CD8+ T cell immunosurveillance.
Publication TypeJournal Article
Year of Publication2011
AuthorsDolan BP, Li L, Veltri CA, Ireland CM, Bennink JR, Yewdell JW
JournalJournal of immunology (Baltimore, Md. : 1950)
Volume186
Issue4
Pagination2065-72
Date Published2011 Feb 15
ISSN1550-6606
KeywordsAnimals, Antigen Presentation, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Cell Membrane Permeability, Female, Green Fluorescent Proteins, H-2 Antigens, Immunologic Surveillance, Mice, Mice, Inbred C57BL, Morpholines, Ovalbumin, Peptide Biosynthesis, Peptide Fragments, Protein Stability, Recombinant Fusion Proteins, Ribosomal Proteins, Signal Transduction
Abstract

To understand better the endogenous sources of MHC class I peptide ligands, we generated an antigenic reporter protein whose degradation is rapidly and reversibly controlled with Shield-1, a cell-permeant drug. Using this system, we demonstrate that defective ribosomal products (DRiPs) represent a major and highly efficient source of peptides and are completely resistant to our attempts to stabilize the protein. Although peptides also derive from nascent Shield-1-sensitive proteins and "retirees" created by Shield-1 withdrawal, these are much less efficient sources on a molar basis. We use this system to identify two drugs--each known to inhibit polyubiquitin chain disassembly--that selectively inhibit presentation of Shield-1-resistant DRiPs. These findings provide the initial evidence for distinct biochemical pathways for presentation of DRiPs versus retirees and implicate polyubiquitin chain disassembly or the actions of deubiquitylating enzymes as playing an important role in DRiP presentation.

DOI10.4049/jimmunol.1003096
Alternate JournalJ. Immunol.