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A more recent version of this article appeared on April 1, 2004
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Submitted on July 18, 2003
Revised on November 13, 2003
Accepted on January 5, 2004
1 Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Armenise Building, Boston, MA 02115, USA
2 Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
3 Infinity Pharmaceuticals, 780 Memorial Drive, Cambridge, MA 02139, USA
4 Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA
* Corresponding author. E-mail address: ploegh{at}hms.harvard.edu.
The mammalian ER-to-cytosol degradation pathway for disposal of misfolded proteins is an attractive target for therapeutic intervention in diseases that are characterized by impaired protein degradation. The ability to do so is hampered by the small number of specific inhibitors available and by our limited understanding of the individual steps involved in this pathway. Cells that express a class I MHC heavy chain-EGFP fusion protein and the HCMV protein US11, which catalyzes dislocation of the class I MHC EGFP reporter, show only little fluorescence. Treatment with proteasome inhibitors increases their fluorescence by stabilizing EGFP-tagged MHC class I molecules (Fiebiger et al., 2002). We used this change in signal intensity as a readout to screen a chemical library of 16,320 compounds and identified two structurally related compounds (eeyarestatin I and II) that interfered with the degradation of both EGFP-HC and its endogenous unmodified class I MHC heavy chain counterpart. Eeyarestatin I also inhibited degradation of a second misfolded type I membrane protein, TCR
. Both compounds stabilize these dislocation substrates in the ER membrane, without preventing proteasomal turnover of cytosolic substrates. The new inhibitors must therefore interfere with a step that precedes proteasomal degradation. The use of eeyarestatin I thus allows the definition of a new intermediate in dislocation.
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