Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease
| Autor: | Russell R. Lonser, Roscoe O. Brady, Masako Chen, Donald Y. Ye, Chunzhang Yang, Zhengping Zhuang, Jie Lu |
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| Rok vydání: | 2011 |
| Předmět: |
Protein Folding
Immunoprecipitation Blotting Western medicine.disease_cause Ubiquitin medicine Humans HSP70 Heat-Shock Proteins Cloning Molecular Mutation Gaucher Disease Multidisciplinary biology Protein Stability Ubiquitination Fibroblasts Biological Sciences Hsp90 Cell biology Histone Deacetylase Inhibitors Biochemistry Proteolysis Mutagenesis Site-Directed biology.protein Unfolded protein response Glucosylceramidase Protein folding Histone deacetylase Glucocerebrosidase HeLa Cells |
| Zdroj: | Proceedings of the National Academy of Sciences. 108:21200-21205 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1119181109 |
| Popis: | Gaucher disease (GD) is caused by a spectrum of genetic mutations within the gene encoding the lysosomal enzyme glucocerebrosidase (GCase). These mutations often lead to misfolded proteins that are recognized by the unfolded protein response system and are degraded through the ubiquitin–proteasome pathway. Modulating this pathway with histone deacetylase inhibitors (HDACis) has been shown to improve protein stability in other disease settings. To identify the mechanisms involved in the regulation of GCase and determine the effects of HDACis on protein stability, we investigated the most prevalent mutations for nonneuronopathic (N370S) and neuronopathic (L444P) GD in cultured fibroblasts derived from GD patients and HeLa cells transfected with these mutations. The half-lives of mutant GCase proteins correspond to decreases in protein levels and enzymatic activity. GCase was found to bind to Hsp70, which directed the protein to TCP1 for proper folding, and to Hsp90, which directed the protein to the ubiquitin–proteasome pathway. Using a known HDACi (SAHA) and a unique small-molecule HDACi (LB-205), GCase levels increased rescuing enzymatic activity in mutant cells. The increase in the quantity of protein can be attributed to increases in protein half-life that correspond primarily with a decrease in degradation rather than an increase in chaperoned folding. HDACis reduce binding to Hsp90 and prevent subsequent ubiquitination and proteasomal degradation without affecting binding to Hsp70 or TCP1. These findings provide insight into the pathogenesis of GD and indicate a potent therapeutic potential of HDAC inhibitors for the treatment of GD and other human protein misfolding disorders. |
| Databáze: | OpenAIRE |
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