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CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy.
Cells ( IF 6 ) Pub Date : 2020-05-26 , DOI: 10.3390/cells9061332
Ssu-Ju Fu , Meng-Chun Hu , Yi-Jheng Peng , Hsin-Yu Fang , Cheng-Tsung Hsiao , Tsung-Yu Chen , Chung-Jiuan Jeng , Chih-Yung Tang

Voltage-gated ClC-2 channels are essential for chloride homeostasis. Complete knockout of mouse ClC-2 leads to testicular degeneration and neuronal myelin vacuolation. Gain-of-function and loss-of-function mutations in the ClC-2-encoding human CLCN2 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.

中文翻译:

CUL4-DDB1-CRBN E3泛素连接酶调节ClC-2氯化物通道的蛋白稳态:对醛固酮增多症和白细胞营养不良的影响。

电压门控的ClC-2通道对于氯化物稳态至关重要。小鼠ClC-2的完全敲除会导致睾丸变性和神经元髓鞘空泡化。编码ClC-2的人类CLCN2的功能获得和功能丧失突变该基因分别与醛固酮增多症和白细胞营养不良等遗传疾病有关。目前尚不清楚ClC-2的蛋白质稳态(蛋白稳态)机制。在这里,我们旨在确定内质网相关的ClC-2降解的分子机制,并探讨疾病相关的异常ClC-2蛋白质稳态的病理生理意义。在异源表达系统以及天然神经元和睾丸细胞中,ClC-2受到cullin-RING E3连接酶介导的多泛素化和蛋白酶体降解的显着调节。cullin 4(CUL4)损伤特异性DNA结合蛋白1(DDB1)-大脑(CRBN)E3泛素连接酶与ClC-2通道共存并促进其降解。靶向CRBN的免疫调节药物来那度胺和cullin E3连接酶抑制剂MLN4924分别促进和减弱ClC-2的蛋白酶体降解。对与疾病相关的ClC-2突变体的分析表明,醛固酮增多症和白细胞营养不良与ClC-2蛋白质稳态的相反变化有关。用来那度胺和MLN4924修饰CUL4 E3连接酶活性可改善与疾病相关的ClC-2蛋白质稳态异常。我们的结果突出了CUL4 E3泛素连接酶在调节ClC-2蛋白质稳态中的重要作用和治疗潜力。用来那度胺和MLN4924修饰CUL4 E3连接酶活性可改善与疾病相关的ClC-2蛋白质稳态异常。我们的结果突出了CUL4 E3泛素连接酶在调节ClC-2蛋白质稳态中的重要作用和治疗潜力。用来那度胺和MLN4924修饰CUL4 E3连接酶活性可改善与疾病相关的ClC-2蛋白质稳态异常。我们的结果突出了CUL4 E3泛素连接酶在调节ClC-2蛋白质稳态中的重要作用和治疗潜力。
更新日期:2020-05-26
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