| Autor: |
Nieves García-Quintáns, Silvia Sacristán, Cristina Márquez-López, Cristina Sánchez-Ramos, Fernando Martinez-de-Benito, David Siniscalco, Andrés González-Guerra, Emilio Camafeita, Marta Roche-Molina, Mariya Lytvyn, David Morera, María I. Guillen, María A. Sanguino, David Sanz-Rosa, Daniel Martín-Pérez, Ricardo Garcia, Juan A. Bernal |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 14, Iss 1, Pp 1-20 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-023-41981-5 |
| Popis: |
Abstract The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic deletion mutations in the desmosomal protein PKP2, here we identify a general mechanism by which PKP2 delocalization restricts actomyosin network organization and cardiac sarcomeric contraction in this untreatable disease. Computational modeling of PKP2 variants reveals that the carboxy-terminal (CT) domain is required for N-terminal domain stabilization, which determines PKP2 cortical localization and function. In mutant PKP2 cells the expression of the interacting protein MYH10 rescues actomyosin disorganization. Conversely, dominant-negative MYH10 mutant expression mimics the pathogenic CT–deletion PKP2 mutant causing actin network abnormalities and right ventricle systolic dysfunction. A chemical activator of non-muscle myosins, 4-hydroxyacetophenone (4-HAP), also restores normal contractility. Our findings demonstrate that activation of MYH10 corrects the deleterious effect of PKP2 mutant over systolic cardiac contraction, with potential implications for ACM therapy. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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