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Intercalated disc protein Xinβ is required for Hippo-YAP signaling in the heart
Haipeng Guo1,2, Yao Wei Lu1, Zhiqiang Lin1,3
1Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 320 Longwood Avenue, Boston, MA, 02115, USA.
Insights
Loss of Xinβ protein disrupts heart function, causing defects in cardiomyocyte proliferation and leading to cardiomyopathy. Xinβ regulates the Hippo-YAP pathway, crucial for cardiac development and function.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cell Biology
Background:
- Intercalated discs (ICDs) are vital for cardiomyocyte coupling and heart contraction.
- Mutations in ICD genes are associated with cardiovascular diseases.
- Xinβ is a newly identified ICD component.
Purpose of the Study:
- To investigate the role of Xinβ in cardiac function and development.
- To elucidate the molecular mechanism linking Xinβ to cardiac signaling pathways.
- To explore Xinβ's involvement in the Hippo-YAP pathway.
Main Methods:
- Analysis of Xinβ knockout mice to study cardiomyocyte proliferation and cardiac function.
- Investigation of Hippo-YAP signaling pathway components (NF2, YAP) in Xinβ mutant hearts.
- Assessment of cardiac function rescue by YAP overexpression in Xinβ deficient mice.
Main Results:
- Loss of Xinβ leads to cardiomyocyte proliferation defects and cardiomyopathy.
- Xinβ recruits NF2 to ICDs, modulating Hippo-YAP signaling.
- Reduced phosphorylated NF2 levels in Xinβ mutant hearts indicate impaired Hippo-YAP signaling.
- Cardiac-specific YAP overexpression rescues cardiac defects in Xinβ knockout mice.
Conclusions:
- Xinβ plays a critical role in cardiac development and function by modulating the Hippo-YAP pathway.
- The Xinβ-NF2-Hippo-YAP axis is essential for maintaining cardiac homeostasis.
- This pathway presents a potential therapeutic target for cardiovascular diseases.
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.
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