title: Inhibition of endoplasmic reticulum-associated degradation rescues native folding in loss of function protein misfolding diseases.
abstract: Lysosomal storage disorders are often caused by mutations that destabilize native folding and impair trafficking of secretory proteins. We demonstrate that endoplasmic reticulum (ER)-associated degradation (ERAD) prevents native folding of mutated lysosomal enzymes in patient-derived fibroblasts from two clinically distinct lysosomal storage disorders, namely Gaucher and Tay-Sachs disease. Prolonging ER retention via ERAD inhibition enhanced folding, trafficking, and activity of these unstable enzyme variants. Furthermore, combining ERAD inhibition with enhancement of the cellular folding capacity via proteostasis modulation resulted in synergistic rescue of mutated enzymes. ERAD inhibition was achieved by cell treatment with small molecules that interfere with recognition (kifunensine) or retrotranslocation (eeyarestatin I) of misfolded substrates. These different mechanisms of ERAD inhibition were shown to enhance ER retention of mutated proteins but were associated with dramatically different levels of ER stress, unfolded protein response activation, and unfolded protein response-induced apoptosis.
authors: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas 77005, USA.
authors: Fan
authors: F
authors: Wang
authors: Wensi
authors: W
authors: Song
authors: Giovanna
authors: G
authors: Brancati
authors: Laura
authors: L
authors: Segatori
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D060746:Endoplasmic Reticulum-Associated Degradation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D016464:Lysosomal Storage Diseases / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: C492847:1-(4-chlorophenyl)-3-(3-(4-chlorophenyl)-5,5-dimethyl-1-(3-(5-nitrofuran-2-yl)allyldienehydrazinocarbonylmethyl)-2-oxoimidazolidin-4-yl)-1-hydroxyurea; D000470:Alkaloids; D006835:Hydrazones; D018832:Molecular Chaperones; C065629:kifunensine; D006918:Hydroxyurea