{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:09:40Z","timestamp":1792098580739,"version":"4.4.0"},"reference-count":75,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T00:00:00Z","timestamp":1590451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["108-2320-B-010-039-MY3"],"award-info":[{"award-number":["108-2320-B-010-039-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["108-2320-B-002-033-MY3"],"award-info":[{"award-number":["108-2320-B-002-033-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM065447"],"award-info":[{"award-number":["R01GM065447"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cells9061332","type":"journal-article","created":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T00:44:02Z","timestamp":1590713042000},"page":"1332","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy"],"prefix":"10.3390","volume":"9","author":[{"given":"Ssu-Ju","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Chun","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Jheng","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Yu","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Tsung","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"},{"name":"Department of Neurology, Taipei Veterans General Hospital, Taipei 12217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Department of Neurology, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6271-5704","authenticated-orcid":false,"given":"Chung-Jiuan","family":"Jeng","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 12212, Taiwan"},{"name":"Brain Research Center, National Yang-Ming University, Taipei 12212, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1065-2865","authenticated-orcid":false,"given":"Chih-Yung","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"},{"name":"Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1093\/hmg\/4.3.407","article-title":"Cloning of a putative human voltage-gated chloride channel (CIC-2) cDNA widely expressed in human tissues","volume":"4","author":"Cid","year":"1995","journal-title":"Hum. 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