Post-transcriptional 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: 25.08.2016
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2016.07.014

Endoplasmic reticulum-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 post-transcriptionally 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 up-regulation 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.