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Carbohydrates act as sorting determinants in ER-associated degradation of tyrosinase
Journal of Cell Science (2004)
  • Daniel Hebert, University of Massachusetts - Amherst
  • T. Wang
  • S. Svedine
  • R. Halaban

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.

Publication Date
June, 2004
Publisher Statement
doi: 10.1242/​jcs.01154
Citation Information
Daniel Hebert, T. Wang, S. Svedine and R. Halaban. "Carbohydrates act as sorting determinants in ER-associated degradation of tyrosinase" Journal of Cell Science Vol. 117 (2004)
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