Cancer Institute A national cancer institute
designated cancer center

Matthew Bogyo

Publication Details

  • Pathways accessory to proteasomal proteolysis are less efficient in major histocompatibility complex class I antigen production JOURNAL OF BIOLOGICAL CHEMISTRY Kessler, B., Hong, X., Petrovic, J., Borodovsky, A., Dantuma, N. P., Bogyo, M., Overkleeft, H. S., Ploegh, H., Glas, R. 2003; 278 (12): 10013-10021


    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 beta-subunits (beta(1), beta(2), and beta(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.

    View details for DOI 10.1074/jbc.M211221200

    View details for Web of Science ID 000181777500004

    View details for PubMedID 12488316

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