2020
DOI: 10.3390/cells9061332
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CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy

Abstract: 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 degradatio… Show more

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Cited by 16 publications
(17 citation statements)
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References 76 publications
(116 reference statements)
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“…Hsp90β is known to stabilize numerous types of client proteins, including E3 ubiquitin ligases that promote degradation of misfolded proteins [ 41 , 42 , 43 ]. For example, Hsp90β directly interacts with and is essential for stabilizing CUL4 [ 34 , 44 ], which serves as an essential component of the CUL4-DDB1-CRBN E3 ubiquitin ligase complex mediating ubiquitination and proteasomal degradation of ClC-2 channels [ 20 ]. Depending on the proteostatic role of Hsp90β in ER quality control, pharmacological suppression of Hsp90β activity may either enhance or reduce protein expression of its client proteins [ 34 , 45 , 46 , 47 ].…”
Section: Resultsmentioning
confidence: 99%
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“…Hsp90β is known to stabilize numerous types of client proteins, including E3 ubiquitin ligases that promote degradation of misfolded proteins [ 41 , 42 , 43 ]. For example, Hsp90β directly interacts with and is essential for stabilizing CUL4 [ 34 , 44 ], which serves as an essential component of the CUL4-DDB1-CRBN E3 ubiquitin ligase complex mediating ubiquitination and proteasomal degradation of ClC-2 channels [ 20 ]. Depending on the proteostatic role of Hsp90β in ER quality control, pharmacological suppression of Hsp90β activity may either enhance or reduce protein expression of its client proteins [ 34 , 45 , 46 , 47 ].…”
Section: Resultsmentioning
confidence: 99%
“…As summarized in the schematic model illustrated in Figure 10 , we propose that ClC-2 protein biogenesis at the ER is promoted by the Hsp90β-Hsc70 chaperone system associated with the co-chaperones HOP, Aha1, and FKBP8. In contrast, leukodystrophy-causing mutations tend to disrupt ClC-2 protein folding at the ER, leading to enhanced ClC-2 polyubiquitination by the CUL4-DDB1-CRBN E3 ubiquitin ligase complex and the ensuing proteasomal degradation [ 20 ].…”
Section: Discussionmentioning
confidence: 99%
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“…Generally, there are three types of ubiquitination modi cation of substrate proteins: a single ubiquitin molecule labelling a single lysine site (single monoubiquitination), multiple ubiquitin molecules labelling a single lysine site (poly monoubiquitination), and ubiquitin chains labelling multiple different lysine residues (polyubiquitination) [31]. If a particular protein has been extensively polyubiquitinated before it is recognized by the proteasome, then the application of lysine-less ubiquitin (UB-K0) will reduce proteolysis [32]. As shown in Fig.…”
Section: Cpne1 Is Elevated In Lung Cancer and Correlates With Poor Sumentioning
confidence: 99%