Nature communications · 2022
NIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.