A ROLE FOR THE UBIQUITIN-DEPENDENT PROTEOLYTIC PATHWAY IN MHC CLASS I-RESTRICTED ANTIGEN PRESENTATION

THE degradation of most cellular proteins starts with their covalent conjugation with ubiquitin1,2. This labels the proteins for rapid hydrolysis to oligopeptides by a (26S) proteolytic complex containing a (20S) degradative particle called the proteasome3,4. Some system in the cytosol also generates antigenic peptides from endogenously synthesized cellular and viral proteins5-10. These peptides bind to newly synthesized class I major histocompatibility complex molecules in the endoplasmic reticulum and peptide/class I complexes are then transported to the cell surface for presentation to cytotoxic T cells11,12. How these peptides are produced is unknown, although a modification that promotes ubiquitin-dependent degradation of a viral protein enhances its presentation with class I13 and indirect evidence suggests a role for proteolytic particles closely resembling and perhaps identical to the proteasome4,12,14,15. Using cells that exhibit a temperature-sensitive defect in ubiquitin conjugation, we report here that nonpermissive temperature inhibited class I-restricted presentation of ovalbumin introduced into the cytosol, but did not affect presentation of an ovalbumin peptide synthesized from a minigene. These results implicate the ubiquitin-dependent proteolytic pathway in the production of antigenic peptides.