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First published online 25 May 2004
doi: 10.1242/jcs.01154
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Research Article |
1 Department of Biochemistry and Molecular Biology, Program in Molecular and Cellular Biology, University of Massachusetts, 710 North Pleasant Street, Amherst, MA 01003, USA
2 Department of Dermatology, Yale University School of Medicine, 15 York Street, New Haven, CT 06520, USA
* Author for correspondence (e-mail: dhebert{at}biochem.umass.edu)
Accepted 12 February 2004
The endoplasmic reticulum (ER) quality-control machinery maintains the fidelity of the maturation process by sorting aberrant proteins for ER-associated protein degradation (ERAD), a process requiring retrotranslocation from the ER lumen to the cytosol and degradation by the proteasome. Here, we assessed the role of N-linked glycans in ERAD by monitoring the degradation of wild-type (Tyr) and albino mutant (Tyr(C85S)) tyrosinase. Initially, mutant tyrosinase was established as a genuine ERAD substrate using intact melanocyte and semi-permeabilized cell systems. Inhibiting mannose trimming or accumulating Tyr(C85S) in a monoglucosylated form led to its stabilization, supporting a role for lectin chaperones in ER retention and proteasomal degradation. In contrast, ablating the lectin chaperone interactions by preventing glucose trimming caused a rapid disappearance of tyrosinase, initially due to the formation of protein aggregates, which were subsequently degraded by the proteasome. The co-localization of aggregated tyrosinase with protein disulfide isomerase and BiP, but not calnexin, supports an ER organization, which aids in protein maturation and degradation. Based on these studies, we propose a model of tyrosinase degradation in which interactions between N-linked glycans and lectin chaperones help to minimize tyrosinase aggregation and also target non-native substrates for retro-translocation and subsequent degradation.
Key words: N-linked glycans, Quality control, Molecular chaperones, Protein aggregation
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