title: Tetrameric Assembly of K+Channels Requires ER-Located Chaperone Proteins.
abstract: Tetrameric assembly of channel subunits in the endoplasmic reticulum (ER) is essential for surface expression and function of K+channels, but the molecular mechanism underlying this process remains unclear. In this study, we found through genetic screening that ER-located J-domain-containing chaperone proteins (J-proteins) are critical for the biogenesis and physiological function of ether-a-go-go-related gene (ERG) K+channels in both Caenorhabditis elegans and human cells. Human J-proteins DNAJB12 and DNAJB14 promoted tetrameric assembly of ERG (and Kv4.2) K+channel subunits through a heat shock protein (HSP) 70-independent mechanism, whereas a mutated DNAJB12 that did not undergo oligomerization itself failed to assemble ERG channel subunits into tetramers in vitro and in C. elegans. Overexpressing DNAJB14 significantly rescued the defective function of human ether-a-go-go-related gene (hERG) mutant channels associated with long QT syndrome (LQTS), a condition that predisposes to life-threatening arrhythmia, by stabilizing the mutated proteins. Thus, chaperone proteins are required for subunit stability and assembly of K+channels.
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Shanghai 200031, PRC.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Shanghai 200031, PRC.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Shanghai 200031, PRC.
authors.forename: Xue
authors.initials: X
authors.lastname: Bai
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: Yang
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Ruan
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: sqcai@ion.ac.cn.
authors.forename: Shi-Qing
authors.initials: SQ
authors.lastname: Cai
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000072237:ERG1 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050958:HSP47 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials; D018832:Molecular Chaperones; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D034622:RNA Interference; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D029742:Caenorhabditis elegans Proteins; C494649:DNAJB12 protein, human; C000623108:DNAJB14 protein, human; D000072237:ERG1 Potassium Channel; D050956:HSP40 Heat-Shock Proteins; D050958:HSP47 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C000606913:KCNH2 protein, human; D018832:Molecular Chaperones; D015221:Potassium Channels; D051672:Shal Potassium Channels; C474006:UNC-103 protein, C elegans; C000623109:dnj-1 protein, C elegans
keywords: C. elegans; J-protein; chaperone protein; hERG; long QT syndrome; potassium channel; protein biogenesis; protein oligomerization; protein trafficking; subunit assembly