Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β
| Autor: | Yi Jheng Peng, Chia Ying Wu, Hsin Ying Hsieh, Shu-Ching Chen, Hao Han Wu, Chih Yung Tang, Tsung-Yu Chen, Jing Jia Huang |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Vesicle-associated membrane protein 8 Proteasome Endopeptidase Complex Patch-Clamp Techniques Myotonia Congenita Leupeptins Genetic Vectors Protein degradation Cysteine Proteinase Inhibitors Small Interfering Transfection Models Biological Article Retinoblastoma-like protein 1 Tacrolimus Binding Proteins 03 medical and health sciences DDB1 Chloride Channels Models Humans HSP90 Heat-Shock Proteins RNA Small Interfering Homeodomain Proteins Multidisciplinary biology urogenital system Tumor Suppressor Proteins Lentivirus Ubiquitination Cullin Proteins Biological Hsp90 3. Good health 030104 developmental biology HEK293 Cells Biochemistry Gene Expression Regulation Ubiquitin ligase complex Proteolysis biology.protein RNA Protein folding Cullin Molecular Chaperones Signal Transduction |
| Zdroj: | Scientific reports, vol 6, iss 1 Scientific Reports |
| Popis: | Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation. |
| Databáze: | OpenAIRE |
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