Inhibitors of the Proteasome Block the Degradation of Most Cell Proteins and the Generation of Peptides Presented on MHC Class I Molecules

Cell. 1994 Sep 9;78(5):761-71. doi: 10.1016/s0092-8674(94)90462-6.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigen Presentation / drug effects*
  • B-Lymphocytes / metabolism
  • Cysteine Endopeptidases / drug effects*
  • Cysteine Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Hematopoietic Stem Cells / metabolism
  • Histocompatibility Antigens Class I / drug effects*
  • Histocompatibility Antigens Class I / metabolism
  • Leupeptins / pharmacology
  • Lymphocytes / drug effects*
  • Lymphocytes / metabolism
  • Mice
  • Molecular Sequence Data
  • Multienzyme Complexes / drug effects*
  • Multienzyme Complexes / metabolism
  • Ovalbumin / metabolism
  • Protease Inhibitors / pharmacology*
  • Proteasome Endopeptidase Complex
  • T-Lymphocytes / metabolism
  • Ubiquitins / metabolism

Substances

  • Histocompatibility Antigens Class I
  • Leupeptins
  • Multienzyme Complexes
  • Protease Inhibitors
  • Ubiquitins
  • acetyl-leucinyl-leucinyl-methional
  • carbobenzoxy-leucyl-leucyl-norvalinal
  • acetylleucyl-leucyl-norleucinal
  • Ovalbumin
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex