García-Quintáns, NievesSantiago-Sacristan, SilviaMárquez-López, CristinaSánchez-Ramos, CristinaMartinez-de-Benito, FernandoSiniscalco, DavidGonzález-Guerra, AndrésCamafeita, EmilioRoche-Molina, MartaLytvyn, MariyaMorera, DavidGuillen, María ISanguino, María ASanz-Rosa, DavidMartin-Perez, DanielGarcia, RicardoBernal, Juan Antonio2024-05-072024-05-072023-10-13Nat Commun. 2023 Oct 13;14(1):6461.http://hdl.handle.net/20.500.12105/19255The 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Arrhythmogenic Right Ventricular DysplasiaCardiomyopathiesHumansActomyosinMutationPlakophilinsAttribution-NonCommercial-NoDerivatives 4.0 Internacional37833253141646110.1038/s41467-023-41981-52041-1723Nature communicationsopen access