Intercalated disc protein Xinβ is required for Hippo-YAP signaling in the heart

Guo, Haipeng; Lu, Yao Wei; Lin, Zhiqiang; Huang, Zhan-Peng; Liu, Jianming; Wang, Yi; Seok, Hee Young; Hu, Xiaoyun; Ma, Qing; Li, Kathryn; Kyselovič, Ján; Wang, Qingchuan; Lin, Jin-Lung; Lin, Juan; Cowan, Douglas B.; Naya, Francisco J.; Chen, Yuguo; Pu, William T.; Wang, Dazhi

doi:10.1038/s41467-020-18379-8

Cited by 18 publications

(15 citation statements)

References 45 publications

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“…Recently, we and others have shown that activating YAP in CMs suppressed the expression of inflammatory genes [16,42]. This study extended our understanding of YAP's role in cardiac homeostasis by systemically interrogating the relationship between YAP and cardiac TLR genes.…”

Section: Yap/tead1 Complex Is a Default Repressor Of Cardiomyocyte Tlr Genessupporting

confidence: 58%

YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes

Gao

Sun

Ercan-Şençiçek

et al. 2021

IJMS

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Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, Tlr8, and Tlr9 in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac Tlr3, Tlr7, Tlr8, and Tlr9 increased with age between neonatal and adult developmental stages, whereas the expression of Tlr5 decreased with age. Furthermore, pathological stress increased the expression levels of Tlr2, Tlr4, Tlr5, Tlr7, Tlr8, and Tlr9. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, and Tlr9. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of Tlr4 depends on a conserved TEAD1 binding motif near Tlr4 transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes.

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Section: Yap/tead1 Complex Is a Default Repressor Of Cardiomyocyte Tlr Genessupporting

confidence: 58%

YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes

Gao

Sun

Ercan-Şençiçek

et al. 2021

IJMS

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“…Wnt signalling was found to be activated in cardiomyocytes which are involved in the fibrofatty replacement of cardiomyocytes in AC (Garcia-Gras et al, 2006). Similarly, the Hippo pathway was found to be controlled by molecules located at the ICD such as YAP (Chen et al, 2014;Guo et al, 2020;Vite et al, 2018). However, it is unclear whether these mechanisms regulate cardiomyocyte adhesion.…”

Section: Adhe S I On Of Interc Al Ated D Isc S Is Ti G Htly Reg Ul At...mentioning

confidence: 99%

“…Among all pathways investigated so far, best evidence has been collected that Wnt and the Hippo pathways are locally controlled at the ICD since YAP has been shown to interact with Pg and β‐catenin and to be regulated by α‐catenin as well (Chen et al, 2014; Vite et al, 2018). Moreover, Xinβ, a regulator of the Hippo pathway, was reported to localize to and thereby to recruit NF2 (Merlin) to ICD (Guo et al, 2020). However, this implies only that signalling molecules located at ICD control cardiomyocyte differentiation and cell fate which is disturbed during cardiac diseases.…”

Section: Adhesion Of Intercalated Discs Is Tightly Regulated By Signa...mentioning

confidence: 99%

Structure and regulation of desmosomes in intercalated discs: Lessons from epithelia

Yeruva

Waschke

2022

Journal of Anatomy

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For electromechanical coupling of cardiomyocytes, intercalated discs (ICDs) are pivotal as highly specialized intercellular contact areas. ICD consists of adhesive contacts, such as desmosomes and adherens junctions (AJs) that are partially intermingled and thereby form an area composita to provide mechanical strength, as well as gap junctions (GJ) and sodium channels for excitation propagation. In contrast, in epithelia, mixed junctions with features of desmosomes and AJs are regarded as transitory primarily during the formation of desmosomes. The anatomy of desmosomes is defined by a typical ultrastructure with dense intracellular plaques anchoring the cadherin‐type adhesion molecules to the intermediate filament cytoskeleton. Desmosomal diseases characterized by impaired adhesive and signalling functions of desmosomal contacts lead to arrhythmogenic cardiomyopathy when affecting cardiomyocytes and cause pemphigus when manifesting in keratinocytes or present as cardiocutaneous syndromes when both cell types are targeted by the disease, which underscores the high biomedical relevance of these cell contacts. Therefore, comparative analyses regarding the structure and regulation of desmosomal contacts in cardiomyocytes and epithelial cells are helpful to better understand disease pathogenesis. In this brief review, we describe the structural properties of ICD compared to epithelial desmosomes and suggest that mechanisms regulating adhesion may at least in part be comparable. Also, we discuss whether phenomena such as hyperadhesion or the bidirectional regulation of desmosomes to serve as signalling hubs in epithelial cells may also be relevant for ICD.

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“…We previously reported that Cypher/ZASP deficiency induced apoptosis, with a striking decrease in cell viability ( 12 ). Recent studies have linked other DCM-associated proteins, such as lamin and Xinβ, to cardiomyocyte proliferation ( 49 , 50 ). Moreover, Cypher interacted with β-catenin mainly through the PDZ domain ( Figures 4G–K ), thereby aligning with the finding that the PDZ domain of Shank3 is responsible for its interaction with β-catenin ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic Analysis Reveals Downstream PKA Effectors of AKAP Cypher/ZASP in the Pathogenesis of Dilated Cardiomyopathy

Pan

Chen

et al. 2021

Front. Cardiovasc. Med.

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Background: Dilated cardiomyopathy (DCM) is a major cause of heart failure worldwide. The Z-line protein Cypher/Z-band alternatively spliced PDZ-motif protein (ZASP) is closely associated with DCM, both clinically and in animal models. Our earlier work revealed Cypher/ZASP as a PKA-anchoring protein (AKAP) that tethers PKA to phosphorylate target substrates. However, the downstream PKA effectors regulated by AKAP Cypher/ZASP and their relevance to DCM remain largely unknown.Methods and Results: For the identification of candidate PKA substrates, global quantitative phosphoproteomics was performed on cardiac tissue from wild-type and Cypher-knockout mice with PKA activation. A total of 216 phosphopeptides were differentially expressed in the Cypher-knockout mice; 31 phosphorylation sites were selected as candidates using the PKA consensus motifs. Bioinformatic analysis indicated that differentially expressed proteins were enriched mostly in cell adhesion and mRNA processing. Furthermore, the phosphorylation of β-catenin Ser675 was verified to be facilitated by Cypher. This phosphorylation promoted the transcriptional activity of β-catenin, and also the proliferative capacity of cardiomyocytes. Immunofluorescence staining demonstrated that Cypher colocalised with β-catenin in the intercalated discs (ICD) and altered the cytoplasmic distribution of β-catenin. Moreover, the phosphorylation of two other PKA substrates, vimentin Ser72 and troponin I Ser23/24, was suppressed by Cypher deletion.Conclusions: Cypher/ZASP plays an essential role in β-catenin activation via Ser675 phosphorylation, which modulates cardiomyocyte proliferation. Additionally, Cypher/ZASP regulates other PKA effectors, such as vimentin Ser72 and troponin I Ser23/24. These findings establish the AKAP Cypher/ZASP as a signalling hub in the progression of DCM.

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Intercalated disc protein Xinβ is required for Hippo-YAP signaling in the heart

Cited by 18 publications

References 45 publications

YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes

YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes

Structure and regulation of desmosomes in intercalated discs: Lessons from epithelia

Phosphoproteomic Analysis Reveals Downstream PKA Effectors of AKAP Cypher/ZASP in the Pathogenesis of Dilated Cardiomyopathy

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