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.

Phosphorylation of the essential myosin light chain (ELC) influence actin-myosin crossbridge cycling in the heart. Here, the authors show upregulated ELC-phosphorylation in systolic heart failure and identify NIMArelated kinase 9 to bind to ELC mediating its calcium-dependent phosphorylation.

Details

Title
NIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart
Author
Müller, Marion 1   VIAFID ORCID Logo  ; Eghbalian, Rose 2 ; Boeckel, Jes-Niels 3   VIAFID ORCID Logo  ; Frese, Karen S. 4   VIAFID ORCID Logo  ; Haas, Jan 4 ; Kayvanpour, Elham 4 ; Sedaghat-Hamedani, Farbod 4   VIAFID ORCID Logo  ; Lackner, Maximilian K. 4 ; Tugrul, Oguz F. 4 ; Ruppert, Thomas 5 ; Tappu, Rewati 4 ; Martins Bordalo, Diana 4 ; Kneuer, Jasmin M. 3   VIAFID ORCID Logo  ; Piekarek, Annika 6   VIAFID ORCID Logo  ; Herch, Sabine 6 ; Schudy, Sarah 4 ; Keller, Andreas 7   VIAFID ORCID Logo  ; Grammes, Nadja 7 ; Bischof, Cornelius 8   VIAFID ORCID Logo  ; Klinke, Anna 8 ; Cardoso-Moreira, Margarida 9   VIAFID ORCID Logo  ; Kaessmann, Henrik 9   VIAFID ORCID Logo  ; Katus, Hugo A. 4 ; Frey, Norbert 4 ; Steinmetz, Lars M. 10   VIAFID ORCID Logo  ; Meder, Benjamin 11   VIAFID ORCID Logo 

1  University Hospital of Heidelberg, Kardiogenetikzentrum Heidelberg, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908); Partner Site Heidelberg/Mannheim, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (GRID:grid.452396.f) (ISNI:0000 0004 5937 5237); University Hospital of the Ruhr-Universität Bochum, Clinic for General and Interventional Cardiology/ Angiology, Herz- und Diabeteszentrum NRW, Bad Oeynhausen, Germany (GRID:grid.418457.b) (ISNI:0000 0001 0723 8327) 
2  University Hospital of Heidelberg, Kardiogenetikzentrum Heidelberg, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908); Partner Site Heidelberg/Mannheim, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (GRID:grid.452396.f) (ISNI:0000 0004 5937 5237) 
3  University of Leipzig, Clinic and Polyclinic for Cardiology, Leipzig, Germany (GRID:grid.9647.c) (ISNI:0000 0004 7669 9786) 
4  Partner Site Heidelberg/Mannheim, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (GRID:grid.452396.f) (ISNI:0000 0004 5937 5237); University of Heidelberg, Department of Medicine III, Heidelberg, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373) 
5  Heidelberg University, CFMP, Core Facility for Mass Spectrometry & Proteomics at ZMBH, Heidelberg, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373); Heidelberg University, ZMBH, Center for Molecular Biology, Heidelberg, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373) 
6  University of Heidelberg, Department of Medicine III, Heidelberg, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373) 
7  Saarland University, Clinical Bioinformatics, Saarbrücken, Germany (GRID:grid.11749.3a) (ISNI:0000 0001 2167 7588); Stanford University Medical School, Department of Neurology and Neurological Sciences, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
8  University Hospital of the Ruhr-Universität Bochum, Clinic for General and Interventional Cardiology/ Angiology, Herz- und Diabeteszentrum NRW, Bad Oeynhausen, Germany (GRID:grid.418457.b) (ISNI:0000 0001 0723 8327) 
9  Heidelberg University, ZMBH, Center for Molecular Biology, Heidelberg, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373) 
10  Partner Site Heidelberg/Mannheim, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (GRID:grid.452396.f) (ISNI:0000 0004 5937 5237); Stanford University Medical School, Stanford Genome Technology Center, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
11  University Hospital of Heidelberg, Kardiogenetikzentrum Heidelberg, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908); Partner Site Heidelberg/Mannheim, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (GRID:grid.452396.f) (ISNI:0000 0004 5937 5237); Stanford University Medical School, Stanford Genome Technology Center, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-33658-2
ProQuest document ID
2726686076
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.