title: Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate.
abstract: Until recently, the degradation of aberrant and unassembled proteins retained in the endoplasmic reticulum (ER) was thought to involve unidentified ER-localized proteases. We now show that the ER-associated degradation (ERAD) of two mutant proteins that accumulate in the ER lumen is inhibited in a proteasome-defective yeast strain and when cytosol from this mutant is used in an in vitro assay. In addition, ERAD is limited in vitro in the presence of the proteasome inhibitors, 3,4-dichloroisocoumarin and lactacystin. Furthermore, we find that an ERAD substrate is exported from ER-derived microsomes, and the accumulation of exported substrate is 2-fold greater when proteasome mutant cytosol is used in place of wild-type cytosol. We conclude that lumenal ERAD substrates are exported from the yeast ER to the cytoplasm for degradation by the proteasome complex.
authors.affiliation: Biology Department, University of Nevada, Reno 89557, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Werner
authors.forename: J L
authors.initials: JL
authors.lastname: Brodsky
authors.forename: A A
authors.initials: AA
authors.lastname: McCracken
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism*; D005800:Genes, Fungal; D049934:Isocoumarins; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000502:physiology*; D013379:Substrate Specificity
chemical_list: D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D005656:Fungal Proteins; D049934:Isocoumarins; D009097:Multienzyme Complexes; C067713:lactacystin; C046235:3,4-dichloroisocoumarin; D000255:Adenosine Triphosphate; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine