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

Nat Commun. 2020 Sep 16;11(1):4666. doi: 10.1038/s41467-020-18379-8.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cardiomyopathy, Dilated / genetics
  • Cell Communication
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression Regulation, Developmental
  • Heart Ventricles / growth & development
  • Hippo Signaling Pathway
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Neurofibromin 2 / genetics
  • Neurofibromin 2 / metabolism
  • Nuclear Proteins / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • LIM Domain Proteins
  • Neurofibromin 2
  • Nf2 protein, mouse
  • Nuclear Proteins
  • XIRP2 protein, human
  • XIRP2 protein, mouse
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • Protein Serine-Threonine Kinases