Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin-43-containing gap junctions in cardiac myocytes
| Autor: | Joseph C. Godoy, Andrea A. Domenighetti, Elizabeth K. Asfaw, Anna R. Busija, Robert S. Ross, Oleksandr Platoshyn, Alice E. Zemljic-Harpf |
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| Rok vydání: | 2014 |
| Předmět: |
Connexin
Cell Communication Biology Cell junction Sudden death Mice Necrosis Phosphatidylinositol 3-Kinases Two-Hybrid System Techniques medicine Animals Myocytes Cardiac Protein Interaction Domains and Motifs Actin Cells Cultured Mice Knockout Cadherin Protein Stability Cell Membrane Gap Junctions Cell Biology Vinculin Actin cytoskeleton Cell biology Protein Transport medicine.anatomical_structure Connexin 43 biology.protein Zonula Occludens-1 Protein Intercalated disc Protein Binding Research Article |
| Zdroj: | Journal of cell science. 127(Pt 5) |
| ISSN: | 1477-9137 |
| Popis: | Vinculin (Vcl) links actin filaments to integrin and cadherin-based cellular junctions. Zonula occludens-1 (ZO-1) binds connexin-43 (Cx43), cadherin and actin. Vcl and ZO-1 anchor the actin cytoskeleton to the sarcolemma. Since loss of Vcl from cardiomyocytes caused mal-distribution of Cx43 and predisposed cardiomyocyte-specific Vcl knockout mice with preserved heart function to arrhythmic sudden death, we hypothesized that Vcl and ZO-1 would interact and that loss of this interaction would destabilize gap junctions. Results: Vcl, Cx43 and ZO-1 colocalized at the intercalated disc (ICD). Loss of cardiomyocyte Vcl caused parallel loss of ZO-1 from ICDs. Vcl co-immunoprecipitated Cx43 and ZO-1, and directly bound ZO-1 in yeast two-hybrid studies. Vcl gene excision in neonatal mouse cardiomyocytes caused reduction of Vcl transcript and protein expression, leading to: 1) decreased protein expression of Cx43, ZO-1, talin, and β1D-integrin, 2) reduced PI3K activation, 3) increased activation of Akt, Erk1, and Erk2, and 4) cardiomyocyte necrosis. Summary: This is the first study showing a direct interaction between Vcl and ZO-1 and illustrates how Vcl plays a critical role in stabilizing gap junctions and myocyte integrity. |
| Databáze: | OpenAIRE |
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