Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules.
Reagents that inhibit the ubiquitin-proteasome proteolytic pathway in cells have not been available. Peptide aldehydes that inhibit major peptidase activities of the 20S and 26S proteasomes are shown to reduce the degradation of protein and ubiquitinated protein substrates by 26S particles. Unlike inhibitors of lysosomal proteolysis, these compounds inhibit the degradation of not only abnormal and short-lived polypeptides but also long-lived proteins in intact cells. We used these agents to test the importance of the proteasome in antigen presentation. When ovalbumin is introduced into the cytosol of lymphoblasts, these inhibitors block the presentation on MHC class I molecules of an ovalbumin-derived peptide by preventing its proteolytic generation. By preventing peptide production from cell proteins, these inhibitors block the assembly of class I molecules. Therefore, the proteasome catalyzes the degradation of the vast majority of cell proteins and generates most peptides presented on MHC class I molecules.
Rock
K L
KL
Division of Lymphocyte Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Gramm
C
C
Rothstein
L
L
Clark
K
K
Stein
R
R
Dick
L
L
Hwang
D
D
Goldberg
A L
AL
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D001402:B-Lymphocytes / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000187:drug effects* / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000187:drug effects* / Q000378:metabolism; D010047:Ovalbumin / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D013601:T-Lymphocytes / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D007976:Leupeptins; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D014452:Ubiquitins; C089487:acetyl-leucinyl-leucinyl-methional; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; C063261:acetylleucyl-leucyl-norleucinal; D010047:Ovalbumin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex