https://scholars.lib.ntu.edu.tw/handle/123456789/594569
標題: | Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect | 作者: | Fu, Ssu-Ju MENG-CHUN HU Hsiao, Cheng-Tsung Cheng, An-Ting Chen, Tsung-Yu Jeng, Chung-Jiuan CHIH-YUNG TANG |
關鍵字: | 17-AAG; channelopathy; chaperone; co-chaperone; protein quality control; proteostasis | 公開日期: | 30-五月-2021 | 出版社: | MDPI | 卷: | 22 | 期: | 11 | 來源出版物: | International journal of molecular sciences | 摘要: | The ClC-2 channel plays a critical role in maintaining ion homeostasis in the brain and the testis. Loss-of-function mutations in the ClC-2-encoding human CLCN2 gene are linked to the white matter disease leukodystrophy. Clcn2-deficient mice display neuronal myelin vacuolation and testicular degeneration. Leukodystrophy-causing ClC-2 mutant channels are associated with anomalous proteostasis manifesting enhanced endoplasmic reticulum (ER)-associated degradation. The molecular nature of the ER quality control system for ClC-2 protein remains elusive. In mouse testicular tissues and Leydig cells, we demonstrated that endogenous ClC-2 co-existed in the same protein complex with the molecular chaperones heat shock protein 90β (Hsp90β) and heat shock cognate protein (Hsc70), as well as the associated co-chaperones Hsp70/Hsp90 organizing protein (HOP), activator of Hsp90 ATPase homolog 1 (Aha1), and FK506-binding protein 8 (FKBP8). Further biochemical analyses revealed that the Hsp90β-Hsc70 chaperone/co-chaperone system promoted mouse and human ClC-2 protein biogenesis. FKBP8 additionally facilitated membrane trafficking of ClC-2 channels. Interestingly, treatment with the Hsp90-targeting small molecule 17-allylamino-17-demethoxygeldanamycin (17-AAG) substantially boosted ClC-2 protein expression. Also, 17-AAG effectively increased both total and cell surface protein levels of leukodystrophy-causing loss-of-function ClC-2 mutant channels. Our findings highlight the therapeutic potential of 17-AAG in correcting anomalous ClC-2 proteostasis associated with leukodystrophy. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/594569 | ISSN: | 16616596 | DOI: | 10.3390/ijms22115859 | SDG/關鍵字: | adenosine triphosphatase; cell surface protein; chaperone; chloride channel; clc 2 chloride channel; complementary DNA; heat shock cognate protein 70; heat shock protein 90; heat shock protein 90 beta; short hairpin RNA; tanespimycin; unclassified drug; Ahsa1 protein, mouse; benzoquinone derivative; chaperone; chloride channel; ClC-2 chloride channels; fk 506 binding protein; Fkbp8 protein, mouse; heat shock protein 70; Hsp90b1 protein, mouse; isoprotein; macrocyclic lactam; animal cell; animal tissue; Article; biochemical analysis; biotinylation; cell membrane; cell surface; cell vacuole; cellular distribution; CHO cell line; coimmunoprecipitation; controlled study; embryo; enzyme activity; female; genetic transfection; HEK293T cell line; heterologous expression; human; human cell; immunofluorescence assay; leukodystrophy; Leydig cell; male; mouse; nonhuman; protein depletion; protein expression; protein folding; protein homeostasis; protein stability; quality control; RNA interference; testis tissue; animal; brain; C57BL mouse; Cricetulus; disease model; drug effect; endoplasmic reticulum associated degradation; gene expression regulation; genetics; HEK293 cell line; knockout mouse; metabolism; nerve cell; pathology; Pelizaeus Merzbacher disease; protein homeostasis; signal transduction; Animals; Benzoquinones; Brain; Chloride Channels; CHO Cells; Cricetulus; Disease Models, Animal; Endoplasmic Reticulum-Associated Degradation; Gene Expression Regulation; HEK293 Cells; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Leydig Cells; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Chaperones; Neurons; Pelizaeus-Merzbacher Disease; Protein Isoforms; Proteostasis; Signal Transduction; Tacrolimus Binding Proteins |
顯示於: | 生理學科所 |
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