USP13 antagonizes gp78 to maintain functionality of a chaperone in ER-associated degradation
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.
© 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of data, Analysis and interpretation of data; WMC, Conception and design, Drafting or revising the article, Contributed unpublished essential data or reagents.
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