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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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Main Authors: Müller, Marion (Author) , Eghbalian, Rose (Author) , Boeckel, Jes-Niels (Author) , Frese, Karen S. (Author) , Haas, Jan (Author) , Kayvanpour, Elham (Author) , Sedaghat-Hamedani, Farbod (Author) , Lackner, Maximilian K. (Author) , Tugrul, Oguz Firat (Author) , Ruppert, Thomas (Author) , Tappu, Rewati (Author) , Martins Bordalo, Diana (Author) , Kneuer, Jasmin Marga (Author) , Piekarek, Annika (Author) , Herch, Sabine (Author) , Schudy, Sarah (Author) , Keller, Andreas (Author) , Grammes, Nadja (Author) , Bischof, Cornelius (Author) , Klinke, Anna (Author) , Cardoso-Moreira, Margarida (Author) , Kaessmann, Henrik (Author) , Katus, Hugo (Author) , Frey, Norbert (Author) , Steinmetz, Lars M. (Author) , Meder, Benjamin (Author)
Format: Article (Journal)
Language:English
Published: 20 October 2022
In: Nature Communications
Year: 2022, Volume: 13, Pages: 1-18
ISSN:2041-1723
DOI:10.1038/s41467-022-33658-2
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-022-33658-2
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-022-33658-2
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Author Notes: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, Benjamin Meder
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Summary: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.
Item Description:Gesehen am 14.11.2022
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-022-33658-2

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