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Title

SARS-CoV-2 protein Nsp1 alters actomyosin cytoskeleton and phenocopies arrhythmogenic cardiomyopathy-related PKP2 mutant

AuthorsMárquez-López, Cristina; Roche-Molina, Marta; García-Quintans, Nieves CSIC; Sacristán, Silvia; Siniscalco, David; González-Guerra, Andrés; Camafeita, Emilio; Lytvyn, Mariya; Guillén, María I.; Sanz-Rosa, David; Martín-Pérez, Daniel; Sánchez-Ramos, Cristina; García, Ricardo; Bernal, Juan A.
Issue Date16-Sep-2020
PublisherBioRxiv
AbstractMutations in desmosomal Plakophilin-2 (PKP2) are the most prevalent drivers of arrhythmogenic cardiomyopathy (ACM) and a common cause of sudden cardiac death in young athletes. However, partner proteins that elucidate PKP2 cellular mechanism to understand 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 the 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 the viral Nsp1 hijacks PKP2 into the cytoplasm and mimics the effect of delocalized R735X mutant. These results demonstrate that cytoplasmic PKP2, wildtype or mutant, induces the collapse of the actomyosin network, since shRNA-PKP2 knockdown maintains the cell structure, validating a critical role of PKP2 localization in the regulation of actomyosin architecture. The fact that Nsp1 and PKP2 mutant 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 survival prognosis.
Publisher version (URL)https://doi.org/10.1101/2020.09.14.296178
URIhttp://hdl.handle.net/10261/219896
DOIhttp://dx.doi.org/10.1101/2020.09.14.296178
Appears in Collections:(ICMM) Artículos
(VICYT) Colección Especial COVID-19
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