LRP6 acts as a scaffold protein in cardiac gap junction assembly

Jun Li; Changming Li; Dandan Liang; Fei Lv; Tianyou Yuan; Erlinda The; Xiue Ma; Yahan Wu; Lixiao Zhen; Duanyang Xie; Shiyi Wang; Yuan Liu; Jian Huang; Jingyi Shi; Yi Liu; Dan Shi; Liang Xu; Li Lin; Luying Peng; Jianmin Cui; Weidong Zhu; Yi-Han Chen

doi:10.1038/ncomms11775

LRP6 acts as a scaffold protein in cardiac gap junction assembly

Nat Commun. 2016 Jun 2:7:11775. doi: 10.1038/ncomms11775.

Authors

Jun Li^{1

2}, Changming Li^{1

3}, Dandan Liang^{1

2}, Fei Lv^{1

3}, Tianyou Yuan^{1

3}, Erlinda The^{1

3}, Xiue Ma^{1

3}, Yahan Wu^{1

3}, Lixiao Zhen^{1

3}, Duanyang Xie^{1

3}, Shiyi Wang^{1

3}, Yuan Liu^{1

3}, Jian Huang^{1

3}, Jingyi Shi⁴, Yi Liu^{1

2}, Dan Shi^{1

2}, Liang Xu^{1

2}, Li Lin^{1

2}, Luying Peng⁵, Jianmin Cui⁴, Weidong Zhu^{1

3}, Yi-Han Chen^{1

2

3

5}

Affiliations

¹ Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
² Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
³ Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
⁴ Cardiac Bioelectricity and Arrhythmia Center, and Department of Biomedical Engineering, Washington University, St Louis, Missouri 63130, USA.
⁵ Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arrhythmias, Cardiac / genetics*
Arrhythmias, Cardiac / metabolism
Arrhythmias, Cardiac / physiopathology
Connexin 43 / genetics
Connexin 43 / metabolism
Echocardiography
Endoplasmic Reticulum / metabolism
Endoplasmic Reticulum / ultrastructure
Gap Junctions / metabolism*
Gap Junctions / ultrastructure
Gene Expression Regulation
Golgi Apparatus / metabolism
Golgi Apparatus / ultrastructure
Heart Ventricles / metabolism*
Heart Ventricles / pathology
Low Density Lipoprotein Receptor-Related Protein-6 / deficiency
Low Density Lipoprotein Receptor-Related Protein-6 / genetics*
Mice
Mice, Knockout
Myocardium / metabolism*
Myocardium / pathology
Myocytes, Cardiac / metabolism*
Myocytes, Cardiac / pathology
Organ Culture Techniques
Primary Cell Culture
Protein Transport
Rats
Rats, Sprague-Dawley
Signal Transduction
Wnt Proteins / genetics
Wnt Proteins / metabolism
beta Catenin / genetics
beta Catenin / metabolism

Substances

Connexin 43
Ctnnb1 protein, rat
Gja1 protein, rat
Low Density Lipoprotein Receptor-Related Protein-6
Lrp6 protein, mouse
Wnt Proteins
beta Catenin