title: Posttranscriptional Regulation of Glycoprotein Quality Control in the Endoplasmic Reticulum Is Controlled by the E2 Ub-Conjugating Enzyme UBC6e.
abstract: 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.
authors: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors: Masatoshi
authors: M
authors: Hagiwara
authors: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors: Jingjing
authors: J
authors: Ling
authors: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors: Paul-Albert
authors: PA
authors: Koenig
authors: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: ploegh@wi.mit.edu.
authors: Hidde L
authors: HL
authors: Ploegh
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D037102:Lectins / Q000235:genetics* / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D044763:Ubiquitin-Conjugating Enzymes / Q000172:deficiency / Q000235:genetics*; D056811:Unfolded Protein Response
chemical_list: C513305:DERL2 protein, human; C486654:EDEM1 protein, human; D037102:Lectins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C098898:OS9 protein, human; D011506:Proteins; C117384:SEL1L protein, human; C489967:UBE2J1 protein, human; D044763:Ubiquitin-Conjugating Enzymes