ABSTRACT
Mutations in desmosomal Plakophilin-2 (PKP2) are the most prevalent drivers of arrhythmogenic-cardiomyopathy (ACM) and a common cause of sudden death in young athletes. However, partner proteins that elucidate PKP2 cellular mechanism behind cardiac dysfunction in ACM are mostly unknown. Here we identify the actin-based motor proteins Myh9 and Myh10 as key PKP2 interactors and demonstrate that expression of the ACM-related PKP2 mutant R735X alters actin fiber organization and cell mechanical stiffness. We also show that SARS-CoV-2 Nsp1 protein acts similarly to this known pathogenic R735X mutant, altering the actomyosin component distribution on cardiac cells. Our data reveal that Nsp1 hijacks PKP2 into the cytoplasm and mimics the effect of delocalized R735X mutant. These results demonstrate that cytoplasmic PKP2 drives actomyosin deregulation and structural collapse, validating a critical role of PKP2 localization in the regulation of actomyosin architecture. The fact that Nsp1 and R735X share similar phenotypes also suggests that direct SARS-CoV-2 heart infection could induce a transient ACM-like disease in COVID-19 patients, which may contribute to right ventricle dysfunction, observed in patients with poor prognosis.