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USP13 antagonizes gp78 to maintain functionality of a chaperone in ER-associated degradation

Liu, Yanfen and Soetandyo, Nia and Lee, Jin-gu and Liu, Liping and Xu, Yue and Clemons, William M., Jr. and Ye, Yihong (2014) USP13 antagonizes gp78 to maintain functionality of a chaperone in ER-associated degradation. eLife, 2014 (3). Art. No. e01369. ISSN 2050-084X. PMCID PMC3889402. https://resolver.caltech.edu/CaltechAUTHORS:20140114-135905566

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Abstract

Physiological adaptation to proteotoxic stress in the endoplasmic reticulum (ER) requires retrotranslocation of misfolded proteins into the cytoplasm for ubiquitination and elimination by ER-associated degradation (ERAD). A surprising paradox emerging from recent studies is that ubiquitin ligases (E3s) and deubiquitinases (DUBs), enzymes with opposing activities, can both promote ERAD. Here we demonstrate that the ERAD E3 gp78 can ubiquitinate not only ERAD substrates, but also the machinery protein Ubl4A, a key component of the Bag6 chaperone complex. Remarkably, instead of targeting Ubl4A for degradation, polyubiquitination is associated with irreversible proteolytic processing and inactivation of Bag6. Importantly, we identify USP13 as a gp78-associated DUB that eliminates ubiquitin conjugates from Ubl4A to maintain the functionality of Bag6. Our study reveals an unexpected paradigm in which a DUB prevents undesired ubiquitination to sharpen substrate specificity for an associated ubiquitin ligase partner and to promote ER quality control.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.7554/eLife.01369DOIArticle
http://elife.elifesciences.org/content/3/e01369PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889402/PubMed CentralArticle
ORCID:
AuthorORCID
Clemons, William M., Jr.0000-0002-0021-889X
Additional Information:© 2014 eLife Sciences Publications. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Received: 14 August 2013; Accepted: 03 December 2013; Published: 14 January 2014. We thank R Deshaies (Caltech), S Fang and M Monteiro (University of Maryland) for plasmids, T Rapoport (Harvard Medical School) for anti-Sec61β antibodies, and T Rapoport and W Prinz for critical reading of the manuscript. Funding: National Institutes of Health Intramural Research Program. The funder had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Author contributions: YL, YY, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article; NS, JL, LL, YX, Acquisition of data, Analysis and interpretation of data; WMC, Conception and design, Drafting or revising the article, Contributed unpublished essential data or reagents.
Funders:
Funding AgencyGrant Number
NIH Intramural Research ProgramUNSPECIFIED
Issue or Number:3
PubMed Central ID:PMC3889402
Record Number:CaltechAUTHORS:20140114-135905566
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140114-135905566
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:43362
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:15 Jan 2014 00:02
Last Modified:03 Oct 2019 06:07

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