Posttranscriptional Regulation of Glycoprotein Quality Control in the Endoplasmic Reticulum Is Controlled by the E2 Ub-Conjugating Enzyme UBC6e

• Published in: Molecular cell Vol. 63; no. 5; pp. 753 - 767
• Main Authors: Hagiwara, Masatoshi, Ling, Jingjing, Koenig, Paul-Albert, Ploegh, Hidde L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2016
• Subjects: Animals; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum-Associated Degradation; Fibroblasts - cytology; Fibroblasts - metabolism; Genetic Vectors - chemistry; Genetic Vectors - metabolism; Glycosylation; HEK293 Cells; Humans; Lectins - genetics; Lectins - metabolism; Lentivirus - genetics; Lentivirus - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Protein Processing, Post-Translational; Proteins - genetics; Proteins - metabolism; Proteolysis; Ubiquitin-Conjugating Enzymes - deficiency; Ubiquitin-Conjugating Enzymes - genetics; Unfolded Protein Response
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2016.07.014

ER-associated degradation (ERAD) is essential for protein quality control in the ER, not only when the ER is stressed, but also at steady state. We report a new layer of homeostatic control, in which ERAD activity itself is regulated posttranscriptionally and independently of the unfolded protein response by adjusting the endogenous levels of EDEM1, OS-9, and SEL1L (ERAD enhancers). Functional UBC6e requires its precise location in the ER to form a supramolecular complex with Derlin2. This complex targets ERAD enhancers for degradation, a function that depends on UBC6e’s enzymatic activity. Ablation of UBC6e causes upregulation of active ERAD enhancers and so increases clearance not only of terminally misfolded substrates, but also of wild-type glycoproteins that fold comparatively slowly in vitro and in vivo. The levels of proteins that comprise the ERAD machinery are thus carefully tuned and adjusted to prevailing needs. [Display omitted] •Deletion of UBC6e upregulates selective ERAD enhancers without activation of the UPR•Levels of ERAD enhancers are controlled by UBC6e-containing complexes•UBC6e deficiency causes hyperactive ERAD through functional ERAD enhancers•Slow folding glycoprotein is more rapidly degraded in UBC6e−/− cells and mice Hagiwara et al. describe a new layer of ERAD control exerted by the ER-resident E2 ubiquitin-conjugating enzyme, UBC6e. Functional EDEM1, OS-9, and SEL1L accumulate in UBC6e-deficient cells and not only accelerate degradation of misfolded ERAD substrates, but also lead to premature degradation of normal glycoproteins that fold comparatively slowly.