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J. Biol. Chem., Vol. 278, Issue 12, 10013-10021, March 21, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/12/10013    most recent M211221200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kessler, B. Articles by Glas, R. Search for Related Content PubMed PubMed Citation Articles by Kessler, B. Articles by Glas, R. Social Bookmarking                      What's this?

Pathways Accessory to Proteasomal Proteolysis Are Less Efficient in Major Histocompatibility Complex Class I Antigen Production^*

Benedikt Kessler^§¶, Xu Hong^§, Jelena Petrovic, Anna Borodovsky^**, Nico P. Dantuma, Matthew Bogyo^§§, Herman S. Overkleeft^¶¶, Hidde Ploegh, and Rickard Glas

From the  Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,  Mikrobiologiskt och Tumôr Biologiskt Centrum, Karolinska Institutet, Stockholm S-171 77, Sweden, and the ^§§ Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143

Degradation of cytosolic proteins depends largely on the proteasome, and a fraction of the cleavage products are presented as major histocompatibility complex (MHC) class I-bound ligands at the cell surface of antigen presenting cells. Proteolytic pathways accessory to the proteasome contribute to protein turnover, and their up-regulation may complement the proteasome when proteasomal proteolysis is impaired. Here we show that reduced reliance on proteasomal proteolysis allowed a reduced efficiency of MHC class I ligand production, whereas protein turnover and cellular proliferation were maintained. Using the proteasomal inhibitor adamantane-acetyl-(6-aminohexanoyl)3-(leucinyl)3-vinyl-(methyl)-sulphone, we show that covalent inhibition of all three types of proteasomal -subunits (₁, ₂, and ₅) was compatible with continued growth in cells that up-regulate accessory proteolytic pathways, which include cytosolic proteases as well as deubiquitinating enzymes. However, under these conditions, we observed poor assembly of H-2D^b molecules and inhibited presentation of endogenous tumor antigens. Thus, the tight link between protein turnover and production of MHC class I ligands can be broken by enforcing the substitution of the proteasome with alternative proteolytic pathways.

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