The mechanical regulation of RNA binding protein hnRNPC in the failing heart

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Authors

MARTINO Fabiana VARADARAJAN Nandan Mysore PERESTRELO Ana Rubina HEJRET Václav DURIKOVA Helena VUKIĆ Dragana HORVATH Vladimir CAVALIERI Francesca CARUSO Frank ALBIHLAL Waleed S GERBER Andre P O'CONNELL Mary Anne VAŇÁČOVÁ Štěpánka PAGLIARI Stefania FORTE Giancarlo

Year of publication 2022
Type Article in Periodical
Magazine / Source Science Translational Medicine
MU Faculty or unit

Central European Institute of Technology

Citation
Web https://www.science.org/doi/10.1126/scitranslmed.abo5715
Doi http://dx.doi.org/10.1126/scitranslmed.abo5715
Keywords Extracellular Matrix; Heart Failure; Heterogeneous-Nuclear Ribonucleoprotein Group C; Humans
Description Cardiac pathologies are characterized by intense remodeling of the extracellular matrix (ECM) that eventually leads to heart failure. Cardiomyocytes respond to the ensuing biomechanical stress by reexpressing fetal contractile proteins via transcriptional and posttranscriptional processes, such as alternative splicing (AS). Here, we demonstrate that the heterogeneous nuclear ribonucleoprotein C (hnRNPC) is up-regulated and relocates to the sarcomeric Z-disc upon ECM pathological remodeling. We show that this is an active site of localized translation, where the ribonucleoprotein associates with the translation machinery. Alterations in hnRNPC expression, phosphorylation, and localization can be mechanically determined and affect the AS of mRNAs involved in mechanotransduction and cardiovascular diseases, including Hippo pathway effector Yes-associated protein 1. We propose that cardiac ECM remodeling serves as a switch in RNA metabolism by affecting an associated regulatory protein of the spliceosome apparatus. These findings offer new insights on the mechanism of mRNA homeostatic mechanoregulation in pathological conditions.
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