TitleInhibition of the Deubiquitinase Usp14 Diminishes Direct MHC Class I Antigen Presentation.
Publication TypeJournal Article
Year of Publication2018
AuthorsPalmer, AL, de Jong, A, Leestemaker, Y, Geurink, PP, Wijdeven, RH, Ovaa, H, Dolan, BP
JournalJ Immunol
Date Published2018 02 01
KeywordsAnimals, Antigen Presentation, Cell Line, Tumor, Histocompatibility Antigens Class I, Mice, Peptides, Protein Biosynthesis, Proteolysis, Pyrroles, Pyrrolidines, T-Lymphocytes, Cytotoxic, Ubiquitin Thiolesterase

Infected or transformed cells must present peptides derived from endogenous proteins on MHC class I molecules to be recognized and targeted for elimination by Ag-specific cytotoxic T cells. In the first step of peptide generation, proteins are degraded by the proteasome. In this study, we investigated the role of the ubiquitin-specific protease 14 (Usp14), a proteasome-associated deubiquitinase, in direct Ag presentation using a ligand-stabilized model protein expressed as a self-antigen. Chemical inhibition of Usp14 diminished direct presentation of the model antigenic peptide, and the effect was especially pronounced when presentation was restricted to the defective ribosomal product (DRiP) form of the protein. Additionally, presentation specifically from DRiP Ags was diminished by expression of a catalytically inactive form of Usp14. Usp14 inhibition did not appreciably alter protein synthesis and only partially delayed protein degradation as measured by a slight increase in the half-life of the model protein when its degradation was induced. Taken together, these data indicate that functional Usp14 enhances direct Ag presentation, preferentially of DRiP-derived peptides, suggesting that the processing of DRiPs is in some ways different from other forms of Ag.

Alternate JournalJ Immunol
PubMed ID29282303
PubMed Central IDPMC5782819
Grant ListR01 AI130059 / AI / NIAID NIH HHS / United States
R56 AI112588 / AI / NIAID NIH HHS / United States