Nuclear decoupling is part of a rapid protein-level cellular response to high-intensity mechanical loading

Gilbert, H. T. J., Mallikarjun, V., Dobre, O. , Jackson, M. R. , Pedley, R., Gilmore, A. P., Richardson, S. M. and Swift, J. (2019) Nuclear decoupling is part of a rapid protein-level cellular response to high-intensity mechanical loading. Nature Communications, 10(1), 4149. (doi: 10.1038/s41467-019-11923-1) (PMID:31515493) (PMCID:PMC6742657)

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Studies of cellular mechano-signaling have often utilized static models that do not fully replicate the dynamics of living tissues. Here, we examine the time-dependent response of primary human mesenchymal stem cells (hMSCs) to cyclic tensile strain (CTS). At low-intensity strain (1 h, 4% CTS at 1 Hz), cell characteristics mimic responses to increased substrate stiffness. As the strain regime is intensified (frequency increased to 5 Hz), we characterize rapid establishment of a broad, structured and reversible protein-level response, even as transcription is apparently downregulated. Protein abundance is quantified coincident with changes to protein conformation and post-translational modification (PTM). Furthermore, we characterize changes to the linker of nucleoskeleton and cytoskeleton (LINC) complex that bridges the nuclear envelope, and specifically to levels and PTMs of Sad1/UNC-84 (SUN) domain-containing protein 2 (SUN2). The result of this regulation is to decouple mechano-transmission between the cytoskeleton and the nucleus, thus conferring protection to chromatin.

Item Type:Articles
Additional Information:H.T.J.G. and J.S. were funded by a Biotechnology and Biological Sciences Research Council (BBSRC) David Phillips Fellowship (BB/L024551/1). V.M. was supported by a studentship from the Sir Richard Stapley Educational Trust. O.D. was supported by a Wellcome Institutional Strategic Support Fund (097820/Z/11/B). Proteomics was carried out at the Wellcome Centre for Cell-Matrix Research (WCCMR; 203128/Z/16/Z) Biological Mass Spectrometry Core Facility; RNA-Seq was performed by the Genomic Technologies Core Facility (GTCF); imaging was carried out at the Bioimaging Facility (supported by BBSRC, Wellcome and the University of Manchester Strategic Fund).
Glasgow Author(s) Enlighten ID:Dobre, Dr Oana and Jackson, Dr Mark
Authors: Gilbert, H. T. J., Mallikarjun, V., Dobre, O., Jackson, M. R., Pedley, R., Gilmore, A. P., Richardson, S. M., and Swift, J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Nature Communications 10(1):4149)
Publisher Policy:Reproduced under a Creative Commons License

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