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.
Highlights
Low-density lipoprotein receptor-related protein 6 (LRP6) is a Wnt co-receptor in the canonical Wnt/b-catenin signalling
LRP6 co-precipitated with connexin 43 (Cx43) (Fig. 1e), which verified the physical interactions between endogenous LRP6 and Cx43
It is worth noting that knockdown of Lrp[5] in neonatal rat ventricular myocytes (NRVMs) did not change Cx43 protein expression and gap junction formation, neither did LRP5 overexpression counteract the downregulation of Cx43 caused by LRP6 deficiency (Supplementary Fig. 3). These results indicate that LRP6 regulates the protein expression of Cx43, thereby affecting Cx43-dependent gap junction formation and function in cardiomyocytes
Summary
Low-density lipoprotein receptor-related protein 6 (LRP6) is a Wnt co-receptor in the canonical Wnt/b-catenin signalling. 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. Given the central regulatory role of LRP6 in mediating the activation of the Wnt/b-catenin pathway[4,5], germ-line knockout of Lrp[6] impairs Wnt signal transduction, thereby causing embryonic lethality in mice[12]. Reduction of LRP6 induced the retention of newly synthesized Cx43 in the endoplasmic reticulum (ER) and thereby promoted the lysosomal degradation of immature Cx43 proteins, which resulted in the impaired formation and function of gap junctions. This study identified the novel scaffolding role of LRP6 in controlling intracellular Cx43 traffic and gap junction formation in the heart
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