NIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart

To adapt to changing hemodynamic demands, regulatory mechanisms modulate actin-myosin-kinetics by calcium-dependent and -independent mechanisms. We investigate the posttranslational modification of human essential myosin light chain (ELC) and identify NIMA-related kinase 9 (NEK9) to interact with EL...

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Detalles Bibliográficos
Autores principales: Müller, Marion, Eghbalian, Rose, Boeckel, Jes-Niels, Frese, Karen S., Haas, Jan, Kayvanpour, Elham, Sedaghat-Hamedani, Farbod, Lackner, Maximilian K., Tugrul, Oguz F., Ruppert, Thomas, Tappu, Rewati, Martins Bordalo, Diana, Kneuer, Jasmin M., Piekarek, Annika, Herch, Sabine, Schudy, Sarah, Keller, Andreas, Grammes, Nadja, Bischof, Cornelius, Klinke, Anna, Cardoso-Moreira, Margarida, Kaessmann, Henrik, Katus, Hugo A., Frey, Norbert, Steinmetz, Lars M., Meder, Benjamin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9585074/
https://www.ncbi.nlm.nih.gov/pubmed/36266340
http://dx.doi.org/10.1038/s41467-022-33658-2
Descripción
Sumario:To adapt to changing hemodynamic demands, regulatory mechanisms modulate actin-myosin-kinetics by calcium-dependent and -independent mechanisms. We investigate the posttranslational modification of human essential myosin light chain (ELC) and identify NIMA-related kinase 9 (NEK9) to interact with ELC. NEK9 is highly expressed in the heart and the interaction with ELC is calcium-dependent. Silencing of NEK9 results in blunting of calcium-dependent ELC-phosphorylation. CRISPR/Cas9-mediated disruption of NEK9 leads to cardiomyopathy in zebrafish. Binding to ELC is mediated via the protein kinase domain of NEK9. A causal relationship between NEK9 activity and ELC-phosphorylation is demonstrated by genetic sensitizing in-vivo. Finally, we observe significantly upregulated ELC-phosphorylation in dilated cardiomyopathy patients and provide a unique map of human ELC-phosphorylation-sites. In summary, NEK9-mediated ELC-phosphorylation is a calcium-dependent regulatory system mediating cardiac contraction and inotropy.

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