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Inhibition of endoplasmic reticulum-associated degradation rescues native folding in loss of function protein misfolding diseases.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2011 Dec 16; Vol. 286 (50), pp. 43454-64. Date of Electronic Publication: 2011 Oct 17. - Publication Year :
- 2011
-
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.
- Subjects :
- Alkaloids pharmacology
Apoptosis genetics
Apoptosis physiology
Blotting, Western
Cells, Cultured
Endoplasmic Reticulum-Associated Degradation drug effects
Endoplasmic Reticulum-Associated Degradation genetics
Humans
Hydrazones pharmacology
Hydroxyurea analogs & derivatives
Hydroxyurea pharmacology
Lysosomal Storage Diseases genetics
Lysosomal Storage Diseases metabolism
Molecular Chaperones genetics
Molecular Chaperones metabolism
Protein Folding drug effects
Proteostasis Deficiencies genetics
Real-Time Polymerase Chain Reaction
Unfolded Protein Response drug effects
Unfolded Protein Response genetics
Unfolded Protein Response physiology
Endoplasmic Reticulum-Associated Degradation physiology
Proteostasis Deficiencies metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 286
- Issue :
- 50
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22006919
- Full Text :
- https://doi.org/10.1074/jbc.M111.274332