title: Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β.
abstract: Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation.
authors: Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Yi-Jheng
authors: YJ
authors: Peng
authors: Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Jing-Jia
authors: JJ
authors: Huang
authors: Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Hao-Han
authors: HH
authors: Wu
authors: Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Hsin-Ying
authors: HY
authors: Hsieh
authors: Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Chia-Ying
authors: CY
authors: Wu
authors: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors: Shu-Ching
authors: SC
authors: Chen
authors: Neuroscience Center, University of California, Davis, USA.
authors: Tsung-Yu
authors: TY
authors: Chen
authors: Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Chih-Yung
authors: CY
authors: Tang
mesh_terms: D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009224:Myotonia Congenita / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C515652:AHSA1 protein, human; C086321:CLC-1 channel; C114234:CUL4A protein, human; D018118:Chloride Channels; D044842:Cullin Proteins; D015853:Cysteine Proteinase Inhibitors; C471205:FKBP8 protein, human; C476884:HOPX protein, human; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D018398:Homeodomain Proteins; D007976:Leupeptins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D046988:Proteasome Endopeptidase Complex; D022021:Tacrolimus Binding Proteins; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde