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Originally published In Press as doi:10.1074/jbc.M211221200 on December 16, 2002

J. Biol. Chem., Vol. 278, Issue 12, 10013-10021, March 21, 2003
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Pathways Accessory to Proteasomal Proteolysis Are Less Efficient in Major Histocompatibility Complex Class I Antigen Production*

Benedikt KesslerDagger §, Xu Hong§||, Jelena Petrovic||, Anna BorodovskyDagger **, Nico P. Dantuma||Dagger Dagger , Matthew Bogyo§§, Herman S. OverkleeftDagger ¶¶, Hidde PloeghDagger , and Rickard Glas||||||

From the Dagger  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 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-2Db 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.

* This work was supported in part by grants from the National Institutes of Health (to H. P.) and from Cancerfonden and the Swedish Research Council (to R. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Both authors contributed equally to this work.

Supported by a Human Frontier Science Program long-term fellowship.

** Supported by a National Science Foundation graduate student fellowship.

Dagger Dagger Supported by a Swedish Research Council fellowship.

¶¶ Present address: Leiden Inst. of Chemistry, Gorlaeus Laboratory, 2300 RA Leiden, The Netherlands.

|||| To whom correspondence should be addressed: MTC, Karolinska Institutet, Theorells Väg 3, Stockholm S-171 77, Sweden. Tel.: 46-8-58589687; Fax: 46-8-7467637; E-mail: rickard.glas@mtc.ki.se.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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