The Cullin 4A/B-DDB1-Cereblon E3 Ubiquitin Ligase Complex Mediates the Degradation of CLC-1 Chloride Channels
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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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KCNMA1/SLO1 and CLC1 are transmembrane proteins whose CRBN-mediated degradation is thought to occur during membrane trafficking.
“The potassium channel KCNMA1/SLO1 and the chloride channel CLC1 are transmembrane proteins whose CRBN-mediated degradation is thought to occur during membrane trafficking26,27.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [27]
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Self-citationWada, T., Asahi, T., & Sawamura, N. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.06.091 · Cited by 17 · see citing works
Cereblon contributes to cardiac dysfunction by degrading Cav1.2α
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Cereblon: promise and challenges for combating human diseases
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Cereblon Regulates the Proteotoxicity of Tau by Tuning the Chaperone Activity of DNAJA1
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UDP-Glucose: A Cereblon-Dependent Glucokinase Protein Degrader
Cho, J., Miyagawa, A., Yamaguchi, K., Abe, W., Tsugawa, Y., Yamamura, H., & Imai, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169094 · Cited by 10 · see citing works
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Pathomechanisms of a CLCN1 Mutation Found in a Russian Family Suffering From Becker's Myotonia
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Mapping the IM i D ‐dependent cereblon interactome using B io ID ‐proximity labelling
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Cereblon-mediated degradation of the amyloid precursor protein via the ubiquitin-proteasome pathway
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FKBP8 Enhances Protein Stability of the CLC-1 Chloride Channel at the Plasma Membrane
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Self-citationChaperone activity of niflumic acid on ClC-1 chloride channel mutants causing myotonia congenita
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Effects of cereblon on stress-activated redox proteins and core behavior
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Thalidomide – From a Banned Drug to Molecular Glues, PROTACs, and New Concepts in Drug Discovery
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Elucidating the regulation of SPAK and OSR1 kinases by ubiquitylation
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Progress of structurally diverse cereblon (CRBN) ligands and their application in PROTAC degraders
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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)
- PMC
- PMC4448132
- 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
- gold
- doi.org
- 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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