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

Author

Listed:
  • Marion Müller

    (University Hospital of Heidelberg
    Partner Site Heidelberg/Mannheim
    University Hospital of the Ruhr-Universität Bochum)

  • Rose Eghbalian

    (University Hospital of Heidelberg
    Partner Site Heidelberg/Mannheim)

  • Jes-Niels Boeckel

    (University of Leipzig)

  • Karen S. Frese

    (Partner Site Heidelberg/Mannheim
    University of Heidelberg)

  • Jan Haas

    (Partner Site Heidelberg/Mannheim
    University of Heidelberg)

  • Elham Kayvanpour

    (Partner Site Heidelberg/Mannheim
    University of Heidelberg)

  • Farbod Sedaghat-Hamedani

    (Partner Site Heidelberg/Mannheim
    University of Heidelberg)

  • Maximilian K. Lackner

    (Partner Site Heidelberg/Mannheim
    University of Heidelberg)

  • Oguz F. Tugrul

    (Partner Site Heidelberg/Mannheim
    University of Heidelberg)

  • Thomas Ruppert

    (Heidelberg University
    Heidelberg University)

  • Rewati Tappu

    (Partner Site Heidelberg/Mannheim
    University of Heidelberg)

  • Diana Martins Bordalo

    (Partner Site Heidelberg/Mannheim
    University of Heidelberg)

  • Jasmin M. Kneuer

    (University of Leipzig)

  • Annika Piekarek

    (University of Heidelberg)

  • Sabine Herch

    (University of Heidelberg)

  • Sarah Schudy

    (Partner Site Heidelberg/Mannheim
    University of Heidelberg)

  • Andreas Keller

    (Saarland University
    Stanford University Medical School)

  • Nadja Grammes

    (Saarland University
    Stanford University Medical School)

  • 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
    University of Heidelberg)

  • Norbert Frey

    (Partner Site Heidelberg/Mannheim
    University of Heidelberg)

  • Lars M. Steinmetz

    (Partner Site Heidelberg/Mannheim
    Stanford University Medical School)

  • Benjamin Meder

    (University Hospital of Heidelberg
    Partner Site Heidelberg/Mannheim
    Stanford University Medical School)

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.

Suggested Citation

  • 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 & , 2022. "NIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33658-2
    DOI: 10.1038/s41467-022-33658-2
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    References listed on IDEAS

    as
    1. Margarida Cardoso-Moreira & Jean Halbert & Delphine Valloton & Britta Velten & Chunyan Chen & Yi Shao & Angélica Liechti & Kelly Ascenção & Coralie Rummel & Svetlana Ovchinnikova & Pavel V. Mazin & Io, 2019. "Gene expression across mammalian organ development," Nature, Nature, vol. 571(7766), pages 505-509, July.
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