CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy
Journal
Cells
Journal Volume
9
Journal Issue
6
Date Issued
2020
Author(s)
Fu, Ssu-Ju
Peng, Yi-Jheng
Fang, Hsin-Yu
Hsiao, Cheng-Tsung
Chen, Tsung-Yu
Jeng, Chung-Jiuan
Abstract
gene are linked to the genetic diseases aldosteronism and leukodystrophy, respectively. The protein homeostasis (proteostasis) mechanism of ClC-2 is currently unclear. Here, we aimed to identify the molecular mechanism of endoplasmic reticulum-associated degradation of ClC-2, and to explore the pathophysiological significance of disease-associated anomalous ClC-2 proteostasis. In both heterologous expression system and native neuronal and testicular cells, ClC-2 is subject to significant regulation by cullin-RING E3 ligase-mediated polyubiquitination and proteasomal degradation. The cullin 4 (CUL4)-damage-specific DNA binding protein 1 (DDB1)-cereblon (CRBN) E3 ubiquitin ligase co-exists in the same complex with and promotes the degradation of ClC-2 channels. The CRBN-targeting immunomodulatory drug lenalidomide and the cullin E3 ligase inhibitor MLN4924 promotes and attenuates, respectively, proteasomal degradation of ClC-2. Analyses of disease-related ClC-2 mutants reveal that aldosteronism and leukodystrophy are associated with opposite alterations in ClC-2 proteostasis. Modifying CUL4 E3 ligase activity with lenalidomide and MLN4924 ameliorates disease-associated ClC-2 proteostasis abnormality. Our results highlight the significant role and therapeutic potential of CUL4 E3 ubiquitin ligase in regulating ClC-2 proteostasis.
SDGs
Other Subjects
chloride channel; ClC-2 chloride channels; CRBN protein, human; Crbn protein, mouse; CUL4A protein, human; CUL4B protein, human; cullin; DDB1 protein, human; DNA binding protein; polyubiquitin; signal transducing adaptor protein; ubiquitin protein ligase; animal; biological model; brain disease; C57BL mouse; enzyme specificity; HEK293 cell line; human; hyperaldosteronism; metabolism; pathology; protein degradation; protein homeostasis; ubiquitination; Wistar rat; Adaptor Proteins, Signal Transducing; Animals; Brain Diseases; Chloride Channels; Cullin Proteins; DNA-Binding Proteins; HEK293 Cells; Humans; Hyperaldosteronism; Mice, Inbred C57BL; Models, Biological; Polyubiquitin; Proteolysis; Proteostasis; Rats, Wistar; Substrate Specificity; Ubiquitin-Protein Ligases; Ubiquitination
Publisher
NLM (Medline)
Type
journal article