Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect

Autor: Meng Chun Hu, Chung Jiuan Jeng, Tsung-Yu Chen, Ssu Ju Fu, An Ting Cheng, Cheng Tsung Hsiao, Chih Yung Tang
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
Pelizaeus-Merzbacher Disease
Mice
Benzoquinones
Protein Isoforms
chaperone
17-AAG
Biology (General)
Spectroscopy
Mice
Knockout
Neurons
biology
Chemistry
Brain
Leydig Cells
Endoplasmic Reticulum-Associated Degradation
General Medicine
Hsp90
Computer Science Applications
Cell biology
Co-chaperone
Signal Transduction
QH301-705.5
co-chaperone
Lactams
Macrocyclic
CHO Cells
Article
Catalysis
Tacrolimus Binding Proteins
Inorganic Chemistry
Cricetulus
channelopathy
Chloride Channels
Heat shock protein
medicine
Animals
Humans
HSP70 Heat-Shock Proteins
HSP90 Heat-Shock Proteins
protein quality control
Physical and Theoretical Chemistry
QD1-999
Molecular Biology
proteostasis
urogenital system
Endoplasmic reticulum
Organic Chemistry
Leukodystrophy
medicine.disease
CLC-2 Chloride Channels
Mice
Inbred C57BL
Disease Models
Animal
HEK293 Cells
Proteostasis
Ion homeostasis
Gene Expression Regulation
Chaperone (protein)
biology.protein
Molecular Chaperones
Zdroj: International Journal of Molecular Sciences; Volume 22; Issue 11; Pages: 5859
International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 22, Iss 5859, p 5859 (2021)
ISSN: 1422-0067
DOI: 10.3390/ijms22115859
Popis: 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.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje