Cited by 61Ubiquitin and proteasome pathwaysIon channel regulation and functionMuscle Physiology and Disorders

The Cullin 4A/B-DDB1-Cereblon E3 Ubiquitin Ligase Complex Mediates the Degradation of CLC-1 Chloride Channels

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Chen, Yi-An, Peng, Yi-Jheng, Hu, Meng-Chun, Huang, Jing-Jia, Chien, Yun-Chia, Wu, June-Tai, Chen, Tsung-Yu, Tang, Chih-Yung·2015·Scientific Reports

Abstract

Voltage-gated CLC-1 chloride channels play a critical role in controlling the membrane excitability of skeletal muscles. Mutations in human CLC-1 channels have been linked to the hereditary muscle disorder myotonia congenita. We have previously demonstrated that disease-associated CLC-1 A531V mutant protein may fail to pass the endoplasmic reticulum quality control system and display enhanced protein degradation as well as defective membrane trafficking. Currently the molecular basis of protein degradation for CLC-1 channels is virtually unknown. Here we aim to identify the E3 ubiquitin ligase of CLC-1 channels. The protein abundance of CLC-1 was notably enhanced in the presence of MLN4924, a specific inhibitor of cullin-RING E3 ligases. Subsequent investigation with dominant-negative constructs against specific subtypes of cullin-RING E3 ligases suggested that CLC-1 seemed to serve as the substrate for cullin 4A (CUL4A) and 4B (CUL4B). Biochemical examinations further indicated that CUL4A/B, damage-specific DNA binding protein 1 (DDB1) and cereblon (CRBN) appeared to co-exist in the same protein complex with CLC-1. Moreover, suppression of CUL4A/B E3 ligase activity significantly enhanced the functional expression of the A531V mutant. Our data are consistent with the idea that the CUL4A/B-DDB1-CRBN complex catalyses the polyubiquitination and thus controls the degradation of CLC-1 channels.

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Authors
Chen, Y.-A., Peng, Y.-J., Hu, M.-C., Huang, J.-J., Chien, Y.-C., Wu, J.-T., Chen, T.-Y., & Tang, C.-Y.
Affiliations
  • National Taiwan University (TW)
  • University of California, Davis (US)
Corresponding author
Tang, Chih-Yung
Venue
Scientific Reports
Published
2015-05-29
Volume
5
Issue
1
Pages
10667-10667
ISSN
2045-2322 (ISSN-L)
OpenAlex
W2272879411
Cited by
61
References
66
Citations by year
2026: 2 · 2025: 4 · 2024: 4 · 2023: 1 · 2022: 8 · 2021: 6 · 2020: 13 · 2019: 4 · 2018: 8 · 2017: 4 · 2016: 6 · 2015: 1
FWCI
2.75
Type
journal article
Language
en
Open access
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Ministry of Science and Technology, Taiwan (055-MY3)
  • National Institutes of Health
  • National Institute of General Medical Sciences (R01GM065447)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Keywords
ClC-1 chloride channel, myotonia congenita, CUL4A, CUL4B, DDB1, cereblon, E3 ubiquitin ligase, polyubiquitination, protein degradation, MLN4924, Cullin-RING E3 ligases, skeletal muscle excitability, endoplasmic reticulum quality control
MeSH terms
DNA-Binding Proteins, Humans, Mutation, Myotonia Congenita, Peptide Hydrolases, Chloride Channels, Muscle, Skeletal, Ubiquitin-Protein Ligases, Cullin Proteins, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Proteolysis

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