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J Biol Chem, Vol. 274, Issue 31, 21963-21972, July 30, 1999

26 S Proteasome-mediated Production of an Authentic Major Histocompatibility Class I-restricted Epitope from an Intact Protein Substrate

Sary Ben-ShaharDagger , Arthur KomloshDagger , Eran NadavDagger , Isabella ShakedDagger , Tamar Ziv§, Arie Admon§, George N. DeMartino, and Yuval ReissDagger

From the Dagger  Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel, the § Department of Biology, The Technion-Israel Institute of Technology, Haifa 32000, Israel, and the  Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75235-9040

Peptides displayed on the cell surface by major histocompatibility class I molecules (MHC class I) are generated by proteolytic processing of protein-antigens in the cytoplasm. Initially, antigens are degraded by the 26 S proteasome, most probably following ubiquitination. However, it is unclear whether this proteolysis results in the generation of MHC class I ligands or if further processing is required. To investigate the role of the 26 S proteasome in antigen presentation, we analyzed the processing of an intact antigen by purified 26 S proteasome. A recombinant ornithine decarboxylase was produced harboring the H-2Kb-restricted peptide epitope, derived from ovalbumin SIINFEKL (termed ODC-ova). Utilizing recombinant antizyme to target the antigen to the 26 S proteasome, we found that proteolysis of ODC-ova by the 26 S proteasome resulted in the generation of the Kb-ligand. Mass spectrometry analysis indicated that in addition to SIINFEKL, the N-terminally extended ligand, HSIINFEKL, was also generated. Production of SIINFEKL was linear with time and directly proportional to the rate of ODC-ova degradation. The overall yield of SIINFEKL was approximately 5% of the amount of ODC-ova degraded. The addition of PA28, the 20 S, or the 20 S-PA28 complex to the 26 S proteasome did not significantly affect the yield of the antigenic peptide. These findings demonstrate that the 26 S proteasome can efficiently digest an intact physiological substrate and generate an authentic MHC class I-restricted epitope.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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