title: Endoplasmic reticulum stress contributes to acetylcholine receptor degradation by promoting endocytosis in skeletal muscle cells.
abstract: After binding by acetylcholine released from a motor neuron, a nicotinic acetylcholine receptor at the neuromuscular junction produces a localized end-plate potential, which leads to muscle contraction. Improper turnover and renewal of acetylcholine receptors contributes to the pathogenesis of myasthenia gravis. In the present study, we demonstrate that endoplasmic reticulum (ER) stress contributes to acetylcholine receptor degradation in C2C12 myocytes. We further show that ER stress promotes acetylcholine receptor endocytosis and lysosomal degradation, which was dampened by blocking endocytosis or treating with lysosome inhibitor. Knockdown of ER stress proteins inhibited acetylcholine receptor endocytosis and degradation, while rescue assay restored its endocytosis and degradation, confirming the effects of ER stress on promoting endocytosis-mediated degradation of junction acetylcholine receptors. Thus, our studies identify ER stress as a factor promoting acetylcholine receptor degradation through accelerating endocytosis in muscle cells. Blocking ER stress and/or endocytosis might provide a novel therapeutic approach for myasthenia gravis.
authors.affiliation: Department of Neurology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200336, China; Department of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: lotusdudu@yahoo.com.
authors.forename: Ailian
authors.initials: A
authors.lastname: Du
authors.affiliation: Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai 200025, China.
authors.forename: Shiqian
authors.initials: S
authors.lastname: Huang
authors.affiliation: Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai 200025, China.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200336, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200336, China.
authors.forename: Lixun
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200336, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Ding
authors.affiliation: Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai 200025, China; Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & SJTUSM, Shanghai 200031, China. Electronic address: cxu@shsmu.edu.cn.
authors.forename: Congfeng
authors.initials: C
authors.lastname: Xu
mesh_terms: D002460:Cell Line; D004705:Endocytosis / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism*
chemical_list: D011950:Receptors, Cholinergic
keywords: Acetylcholine receptor; Endocytosis; Endoplasmic reticulum stress; Myasthenia gravis; Protein degradation; Skeletal muscle cells