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. DOI: http://dx.doi.org/10.7554/eLife.01369.001.
journal_name
Elifejournal_title
eLifeauthors
Liu Y,Soetandyo N,Lee JG,Liu L,Xu Y,Clemons WM Jr,Ye Ydoi
10.7554/eLife.01369subject
Has Abstractpub_date
2014-01-01 00:00:00pages
e01369issn
2050-084Xpii
3/0/e01369journal_volume
3pub_type
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