Phosphorylation of endothelial histone H3.3 serine 31 by PKN1 links 
flow-induced signaling to proatherogenic gene expression

Jin, Young-June; Liang, Guozheng; Li, Rui; Wang, Shengpeng; Alnouri, Mohamad Wessam; Bentsen, Mette; Kuenne, Carsten; Guenther, Stefan; Yan, Yang; Li, Yongxin; Wettschureck, Nina; Offermanns, Stefan

doi:10.1038/s44161-024-00593-y

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Phosphorylation of endothelial histone H3.3 serine 31 by PKN1 links flow-induced signaling to proatherogenic gene expression

MPS-Authors

/persons/resource/persons239385

Jin, Young-June
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons251641

Liang, Guozheng
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons248817

Li, Rui
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224209

Wang, Shengpeng
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons261924

Alnouri, Mohamad Wessam
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons248851

Bentsen, Mette
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224382

Kuenne, Carsten
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224128

Guenther, Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224211

Wettschureck, Nina
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224185

Offermanns, Stefan
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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引用

Jin, Y.-J., Liang, G., Li, R., Wang, S., Alnouri, M. W., Bentsen, M., Kuenne, C., Guenther, S., Yan, Y., Li, Y., Wettschureck, N., & Offermanns, S. (2025). Phosphorylation of endothelial histone H3.3 serine 31 by PKN1 links flow-induced signaling to proatherogenic gene expression. NATURE CARDIOVASCULAR RESEARCH, 4(2). doi:10.1038/s44161-024-00593-y.

引用: https://hdl.handle.net/21.11116/0000-0010-F25F-3

要旨

Atherosclerotic lesions develop preferentially in arterial regions exposed to disturbed blood flow, where endothelial cells acquire an inflammatory phenotype. How disturbed flow induces endothelial cell inflammation is incompletely understood. Here we show that histone H3.3 phosphorylation at serine 31 (H3.3S31) regulates disturbed-flow-induced endothelial inflammation by allowing rapid induction of FOS and FOSB, required for inflammatory gene expression. We identified protein kinase N1 (PKN1) as the kinase responsible for disturbed-flow-induced H3.3S31 phosphorylation. Disturbed flow activates PKN1 in an integrin alpha 5 beta 1-dependent manner and induces its translocation into the nucleus, and PKN1 is also involved in the phosphorylation of the AP-1 transcription factor JUN. Mice with endothelium-specific PKN1 loss or endothelial expression of S31 phosphorylation-deficient H.3.3 mutants show reduced endothelial inflammation and disturbed-flow-induced vascular remodeling in vitro and in vivo. Together, we identified a pathway whereby disturbed flow through PKN1-mediated histone phosphorylation and FOS/FOSB induction promotes inflammatory gene expression and vascular inflammation.