LRP6 acts as a scaffold protein in cardiac gap junction assembly

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

doi:10.1038/ncomms11775

Cited by 34 publications

(35 citation statements)

References 36 publications

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“…Here we have studied the biogenesis of Low-density lipoprotein Receptor-related Protein 6 (LRP6), a key component of the canonical Wnt signaling pathway, which has been associated with many human pathologies including cancer, osteoporosis and metabolic diseases (Joiner et al, 2013), but also involved in the formation of gap junctions in cardiomyocytes (Li et al, 2016). LRP6 is a type I membrane protein composed of a large extracellular domain containing multiple ß-propeller and EGF-like domains (MacDonald et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6

Perrody

Abrami

Feldman

et al. 2016

eLife

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Many membrane proteins fold inefficiently and require the help of enzymes and chaperones. Here we reveal a novel folding assistance system that operates on membrane proteins from the cytosolic side of the endoplasmic reticulum (ER). We show that folding of the Wnt signaling coreceptor LRP6 is promoted by ubiquitination of a specific lysine, retaining it in the ER while avoiding degradation. Subsequent ER exit requires removal of ubiquitin from this lysine by the deubiquitinating enzyme USP19. This ubiquitination-deubiquitination is conceptually reminiscent of the glucosylation-deglucosylation occurring in the ER lumen during the calnexin/calreticulin folding cycle. To avoid infinite futile cycles, folded LRP6 molecules undergo palmitoylation and ER export, while unsuccessfully folded proteins are, with time, polyubiquitinated on other lysines and targeted to degradation. This ubiquitin-dependent folding system also controls the proteostasis of other membrane proteins as CFTR and anthrax toxin receptor 2, two poor folders involved in severe human diseases.DOI: http://dx.doi.org/10.7554/eLife.19083.001

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Section: Introductionmentioning

confidence: 99%

Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6

Perrody

Abrami

Feldman

et al. 2016

eLife

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“…In the present study, we observed that LRP6 interacted with N‐cadherin, γ‐catenin, β‐catenin and Cx43, but not with desmoplakin. Li et al reported that LRP6 interacts with Cx43, and LRP6 deficiency causes Cx43 degradation (Li et al, ). However, only few studies have reported LRP6 interaction with other ID proteins.…”

Section: Discussionmentioning

confidence: 99%

“…LRP6 is widely expressed in human and mouse tissues, including the cardiovascular system. Li et al () reported that LRP6 acts as a scaffold protein regulating connexin 43 (Cx43) expression. It was recently found that cardiac‐specific LRP6 knockout induces lethal cardiac dysfunction by activation of dynamin‐related protein 1 (Drp1) (Chen, Li, Wang, et al, ); abnormal structure of the intercalated disk (ID) in LRP6‐deficient hearts was also observed.…”

Section: Introductionmentioning

confidence: 99%

Lipoprotein receptor‐related protein 6 is required to maintain intercalated disk integrity

Wang

Zou

et al. 2019

Genes to Cells

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The intercalated disk (ID), a highly organized adhesion structure connecting neighboring cardiomyocytes, fulfills mechanical and electrical signaling communication to ensure normal heart function. Lipoprotein receptor‐related protein 6 (LRP6) is a co‐receptor inducing canonical Wnt/β‐catenin signaling. It was recently reported that LRP6 deficiency in cardiomyocytes predisposes to arrhythmia independent of Wnt signaling. However, whether LRP6 directly regulates the structure of IDs requires further investigation. The aim of the present study was to explore the role of LRP6 in IDs and the potential underlying mechanisms by inducible cardiac‐specific LRP6 knockout mice. The results revealed that LRP6 was predominately expressed in the cell membrane, including the IDs of cardiomyocytes. Tamoxifen‐inducible cardiac‐specific LRP6 knockout mice displayed overt cardiac dysfunction and disruption of ID structure. Further analysis revealed that cardiac LRP6 deficiency induced the imbalance of ID component proteins, characterized by the sharply decreased expression of connexin 43 (Cx43) and the significantly increased expression of N‐cadherin, desmoplakin and γ‐catenin in tissue lysates or membrane fraction from the left ventricle. STRING database analysis indicated that β‐catenin, but no other ID‐associated proteins, interacted with LRP6. Our immunoprecipitation analysis demonstrated that LRP6 strongly interacted with Cx43, N‐cadherin and γ‐catenin, and weakly interacted with β‐catenin, whereas there was no association with desmoplakin. In response to LRP6 deficiency, the recruitment of β‐ or γ‐catenin to N‐cadherin was increased, but they displayed little interaction with Cx43. In conclusion, LRP6 is required to maintain the integrity of ID structure and the balance of ID proteins, and the interaction between LRP6 and Cx43, N‐cadherin and γ‐catenin may be involved in this process.

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“…Cx43 in cultured neonatal myocytes (as in intact neonatal ventricular myocardium) is distributed around the entire cell perimeter rather than being located at the poles of the cells in IDs in adult myocytes (50)(51)(52). It is plausible that Cdon might regulate the localization of Cx43 through a Wnt-independent pathway, such as N-cadherin or LRP6, because Cdon is localized at the ID and directly interacts with N-cadherin (53) and LRP6 (28), both of which are implicated in proper localization of Cx43 (54)(55)(56)(57). Regardless, the results presented here provide direct evidence of a functional role for Cdon in the control of Cx43 expression and its localization to the ID at the site of end-to-end contacts between cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

Jeong

Kim

Pyun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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On pathological stress, Wnt signaling is reactivated and induces genes associated with cardiac remodeling and fibrosis. We have previously shown that a cell surface receptor Cdon (cell-adhesion associated, oncogene regulated) suppresses Wnt signaling to promote neuronal differentiation however its role in heart is unknown. Here, we demonstrate a critical role of Cdon in cardiac function and remodeling. Cdon is expressed and predominantly localized at intercalated disk in both mouse and human hearts. Cdon-deficient mice develop cardiac dysfunction including reduced ejection fraction and ECG abnormalities.Cdon−/−hearts exhibit increased fibrosis and up-regulation of genes associated with cardiac remodeling and fibrosis. Electrical remodeling was demonstrated by up-regulation and mislocalization of the gap junction protein, Connexin 43 (Cx43) inCdon−/−hearts. In agreement with altered Cx43 expression, functional analysis both usingCdon−/−cardiomyocytes and shRNA-mediated knockdown in rat cardiomyocytes shows aberrant gap junction activities. Analysis of the underlying mechanism reveals thatCdon−/−hearts exhibit hyperactive Wnt signaling as evident by β-catenin accumulation and Axin2 up-regulation. On the other hand, the treatment of rat cardiomyocytes with a Wnt activator TWS119 reduces Cdon levels and aberrant Cx43 activities, similarly to Cdon-deficient cardiomyocytes, suggesting a negative feedback between Cdon and Wnt signaling. Finally, inhibition of Wnt/β-catenin signaling by XAV939, IWP2 or dickkopf (DKK)1 prevented Cdon depletion-induced up-regulation of collagen 1a and Cx43. Taken together, these results demonstrate that Cdon deficiency causes hyperactive Wnt signaling leading to aberrant intercellular coupling and cardiac fibrosis. Cdon exhibits great potential as a target for the treatment of cardiac fibrosis and cardiomyopathy.

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LRP6 acts as a scaffold protein in cardiac gap junction assembly

Cited by 34 publications

References 36 publications

Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6

Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6

Lipoprotein receptor‐related protein 6 is required to maintain intercalated disk integrity

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

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