Intercalated disc protein Xin\u03b2 is required for Hippo-YAP signaling in the heart

Haipeng Guo,Francisco Naya,Qing Ma,Da-Zhi Wang,Jenny L.-C Lin,Yi Wang,Xiaoyun Hu,Kathryn Li,Zhiqiang Lin,Jan Kyselovic,Hee Young Seok,William T Pu,Jianming Liu,Douglas B Cowan,Qingchuan Wang,Jim J.-C Lin,Yao Wei Lu,Zhan-Peng Huang,Yuguo Chen

doi:10.1038/s41467-020-18379-8

Abstract

Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Mutations in genes encoding ICD components are linked to cardiovascular diseases. Here, we show that loss of Xinβ, a newly-identified component of ICDs, results in cardiomyocyte proliferation defects and cardiomyopathy. We uncovered a role for Xinβ in signaling via the Hippo-YAP pathway by recruiting NF2 to the ICD to modulate cardiac function. In Xinβ mutant hearts levels of phosphorylated NF2 are substantially reduced, suggesting an impairment of Hippo-YAP signaling. Cardiac-specific overexpression of YAP rescues cardiac defects in Xinβ knock-out mice—indicating a functional and genetic interaction between Xinβ and YAP. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xinβ modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. Consequently, this pathway may represent a therapeutic target for the treatment of cardiovascular diseases.

Highlights

Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart
Consistent with prior studies[4], we found that germline deletion of Xinβ (XinβKO) in mice resulted in postnatal lethality
Gene expression analyses showed that 717 genes were differentially expressed (p < 0.01), with 373 genes increased and 344 genes reduced in Xinβ-knockout mice (XinβKO) mouse hearts (Fig. 1b)

Summary

Introduction

Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xinβ modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. This pathway may represent a therapeutic target for the treatment of cardiovascular diseases. Xinα and Xinβ are primarily located in the ICD of adult cardiomyocytes[8] These proteins play an important role during early cardiac development[4,9] and may be pivotal in the pathogenesis of some forms of heart disease[6]. Genetic and biochemical studies have established that cellular growth and differentiation signals are transmitted through a series of protein kinase cascades to modulate downstream gene expression[12]

Methods

Results

Conclusion