Aberrant substrate engagement of the ER translocon triggers degradation by the Hrd1 ubiquitin ligase
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Rubenstein-2012-Aberrant substrate e.pdf
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Author(s)
Greenblatt, Wesley H.
Rubenstein, Eric M.
Kreft, Stefan G.
Swanson, Robert
Hochstrasser, Mark
Date Issued
June 2012
Journal
Journal of Cell Biology
Publisher
Rockefeller University Press, The
Citation
Rubenstein, E. M. et al. “Aberrant Substrate Engagement of the ER Translocon Triggers Degradation by the Hrd1 Ubiquitin Ligase.” The Journal of Cell Biology 197.6 (2012): 761–773. © 2012 by The Rockefeller University Press
Version
Final published version
Abstract
Little is known about quality control of proteins that aberrantly or persistently engage the endoplasmic reticulum (ER)-localized translocon en route to membrane localization or the secretory pathway. Hrd1 and Doa10, the primary ubiquitin ligases that function in ER-associated degradation (ERAD) in yeast, target distinct subsets of misfolded or otherwise abnormal proteins based primarily on degradation signal (degron) location. We report the surprising observation that fusing Deg1, a cytoplasmic degron normally recognized by Doa10, to the Sec62 membrane protein rendered the protein a Hrd1 substrate. Hrd1-dependent degradation occurred when Deg1-Sec62 aberrantly engaged the Sec61 translocon channel and underwent topological rearrangement. Mutations that prevent translocon engagement caused a reversion to Doa10-dependent degradation. Similarly, a variant of apolipoprotein B, a protein known to be cotranslocationally targeted for proteasomal degradation, was also a Hrd1 substrate. Hrd1 therefore likely plays a general role in targeting proteins that persistently associate with and potentially obstruct the translocon.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
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Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported
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DOI of Published Version
https://doi.org/10.1083/jcb.201203061
