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 ubiquitin. This labels the proteins for rapid hydrolysis to oligopeptides by a (26S) proteolytic complex containing a (20S) degradative particle called the proteasome. Some system in the cytosol also generates antigenic peptides from endogenously synthesized cellular and viral proteins. 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 cells. 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 proteasome. Using cells that exhibit a temperature-sensitive defect in ubiquitin conjugation, we report here that non-permissive 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.
Michalek
M T
MT
Division of Lymphocyte Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Grant
E P
EP
Gramm
C
C
Goldberg
A L
AL
Rock
K L
KL
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D006183:H-2 Antigens / Q000276:immunology / Q000378:metabolism*; D006868:Hydrolysis; D051379:Mice; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010873:Pinocytosis; D013696:Temperature; D014162:Transfection; D014452:Ubiquitins / Q000502:physiology*
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D014452:Ubiquitins; D010047:Ovalbumin