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

Haipeng Guo, Yao Wei Lu, Zhiqiang Lin, Zhan-Peng Huang, Jianming Liu, Yi Wang, Hee Young Seok, Xiaoyun Hu, Qing Ma, Kathryn Li, Jan Kyselovic, Qingchuan Wang, Jenny L.-C. Lin, Jim J.-C. Lin, Douglas B. Cowan, Francisco Naya, Yuguo Chen, William T. Pu and Da-Zhi Wang ()
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Haipeng Guo: Boston Children’s Hospital, Harvard Medical School
Yao Wei Lu: Boston Children’s Hospital, Harvard Medical School
Zhiqiang Lin: Boston Children’s Hospital, Harvard Medical School
Zhan-Peng Huang: Boston Children’s Hospital, Harvard Medical School
Jianming Liu: Boston Children’s Hospital, Harvard Medical School
Yi Wang: Boston Children’s Hospital, Harvard Medical School
Hee Young Seok: Boston Children’s Hospital, Harvard Medical School
Xiaoyun Hu: Boston Children’s Hospital, Harvard Medical School
Qing Ma: Boston Children’s Hospital, Harvard Medical School
Kathryn Li: Boston Children’s Hospital, Harvard Medical School
Jan Kyselovic: Comenius University
Qingchuan Wang: University of Iowa
Jenny L.-C. Lin: University of Iowa
Jim J.-C. Lin: University of Iowa
Douglas B. Cowan: Boston Children’s Hospital, Harvard Medical School
Francisco Naya: Boston University
Yuguo Chen: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Cheeloo College of Medicine, Shandong University
William T. Pu: Boston Children’s Hospital, Harvard Medical School
Da-Zhi Wang: Boston Children’s Hospital, Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18379-8

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