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

Marion Müller, Rose Eghbalian, Jes-Niels Boeckel, Karen S. Frese, Jan Haas, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Maximilian K. Lackner, Oguz F. Tugrul, Thomas Ruppert, Rewati Tappu, Diana Martins Bordalo, Jasmin M. Kneuer, Annika Piekarek, Sabine Herch, Sarah Schudy, Andreas Keller, Nadja Grammes, Cornelius Bischof, Anna Klinke, Margarida Cardoso-Moreira, Henrik Kaessmann, Hugo A. Katus, Norbert Frey, Lars M. Steinmetz and Benjamin Meder ()
Additional contact information
Marion Müller: University Hospital of Heidelberg
Rose Eghbalian: University Hospital of Heidelberg
Jes-Niels Boeckel: University of Leipzig
Karen S. Frese: Partner Site Heidelberg/Mannheim
Jan Haas: Partner Site Heidelberg/Mannheim
Elham Kayvanpour: Partner Site Heidelberg/Mannheim
Farbod Sedaghat-Hamedani: Partner Site Heidelberg/Mannheim
Maximilian K. Lackner: Partner Site Heidelberg/Mannheim
Oguz F. Tugrul: Partner Site Heidelberg/Mannheim
Thomas Ruppert: Heidelberg University
Rewati Tappu: Partner Site Heidelberg/Mannheim
Diana Martins Bordalo: Partner Site Heidelberg/Mannheim
Jasmin M. Kneuer: University of Leipzig
Annika Piekarek: University of Heidelberg
Sabine Herch: University of Heidelberg
Sarah Schudy: Partner Site Heidelberg/Mannheim
Andreas Keller: Saarland University
Nadja Grammes: Saarland University
Cornelius Bischof: University Hospital of the Ruhr-Universität Bochum
Anna Klinke: University Hospital of the Ruhr-Universität Bochum
Margarida Cardoso-Moreira: Heidelberg University
Henrik Kaessmann: Heidelberg University
Hugo A. Katus: Partner Site Heidelberg/Mannheim
Norbert Frey: Partner Site Heidelberg/Mannheim
Lars M. Steinmetz: Partner Site Heidelberg/Mannheim
Benjamin Meder: University Hospital of Heidelberg

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33658-2

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