title: LRP6 acts as a scaffold protein in cardiac gap junction assembly.
abstract: Low-density lipoprotein receptor-related protein 6 (LRP6) is a Wnt co-receptor in the canonical Wnt/β-catenin signalling. Here, we report the scaffold function of LRP6 in gap junction formation of cardiomyocytes. Cardiac LRP6 is spatially restricted to intercalated discs and binds to gap junction protein connexin 43 (Cx43). A deficiency in LRP6 disrupts Cx43 gap junction formation and thereby impairs the cell-to-cell coupling, which is independent of Wnt/β-catenin signalling. The defect in Cx43 gap junction resulting from LRP6 reduction is attributable to the defective traffic of de novo Cx43 proteins from the endoplasmic reticulum to the Golgi apparatus, leading to the lysosomal degradation of Cx43 proteins. Accordingly, the hearts of conditional cardiac-specific Lrp6-knockout mice consistently exhibit overt reduction of Cx43 gap junction plaques without any abnormality in Wnt signalling and are predisposed to lethal arrhythmias. These findings uncover a distinct role of LRP6 as a platform for intracellular protein trafficking.
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Changming
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Liang
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Lv
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Tianyou
authors.initials: T
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Erlinda
authors.initials: E
authors.lastname: The
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Xiue
authors.initials: X
authors.lastname: Ma
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yahan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Lixiao
authors.initials: L
authors.lastname: Zhen
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Duanyang
authors.initials: D
authors.lastname: Xie
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Shiyi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Cardiac Bioelectricity and Arrhythmia Center, and Department of Biomedical Engineering, Washington University, St Louis, Missouri 63130, USA.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Shi
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Shi
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Luying
authors.initials: L
authors.lastname: Peng
authors.affiliation: Cardiac Bioelectricity and Arrhythmia Center, and Department of Biomedical Engineering, Washington University, St Louis, Missouri 63130, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Cui
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Institute of Medical Genetics, Tongji University, Shanghai 200092, China.|Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004452:Echocardiography; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D017629:Gap Junctions / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D061251:Primary Cell Culture; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D018031:Connexin 43; C495268:Ctnnb1 protein, rat; C580592:Gja1 protein, rat; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin