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bioRxiv · 10.1101/2023.04.24.538195

Tension sensing by FAK governs nuclear mechanotransduction, endothelial transcriptome and fate

Akhter, M. Z.·Yazbeck, P.·Tauseef, M.·Anwar, M.·Hossen, F.·Datta, S.·Vellingiri, V.·Joshi, J. C.·Srivastava, N.·Lenzini, S.·Zhou, G.·Lee, J.·Jain, M. K.·Shin, J.-W.·Mehta, D.
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Abstract

Vascular endothelium forms a restrictive barrier to defend the underlying tissue against uncontrolled influx of circulating protein and immune cells. Mechanisms that mediate the transition from restrictive to leaky endothelium, a hallmark of tissue injury exemplified by acute lung injury (ALI), remain elusive. Using endothelial cell (EC)-Fak-/-mice, we show that FAK sensing and transmission of mechanical tension to the EC nucleus governs cell fate. In FAK- deleted EC, increased EC tension induced by Rho kinase caused tyrosine phosphorylation of nuclear envelope protein, emerin at Y74/Y95, and its localization in a nuclear cap. Activated emerin stimulated DNMT3a activity and methylation of the KLF2 promoter, impairing the restrictive EC transcriptome, including S1PR1. Inhibiting emerin phosphorylation or DNMT3a activity enabled KLF2 transcription of S1PR1, rescuing the restrictive EC phenotype in EC-Fak-/- lungs. Thus, FAK sensing of tension transmission to the nucleus is crucial for maintaining a restrictive EC fate and lung homeostasis.

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Akhter, M. Z., Yazbeck, P., Tauseef, M., Anwar, M., Hossen, F., Datta, S., Vellingiri, V., Joshi, J. C., Srivastava, N., Lenzini, S., Zhou, G., Lee, J., Jain, M. K., Shin, J.-W., Mehta, D.. 2023-04-26. Tension sensing by FAK governs nuclear mechanotransduction, endothelial transcriptome and fate. https://doi.org/10.1101/2023.04.24.538195

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