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Cellular senescence is associated with reorganization of the microtubule cytoskeleton

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Abstract

Senescent cells undergo structural and functional changes that affect essentially every aspect of cell physiology. To date, the impact of senescence on the cytoskeleton is poorly understood. This study evaluated the cytoskeleton in two independent cellular models of kidney epithelium senescence. Our work identified multiple senescence-related alterations that impact microtubules and filamentous actin during interphase. Both filamentous systems reorganized profoundly when cells became senescent. As such, microtubule stability increased during senescence, making these filaments more resistant to disassembly in the cold or by nocodazole. Microtubule stabilization was accompanied by enhanced α-tubulin acetylation on lysine 40 and the depletion of HDAC6, the major deacetylase for α-tubulin lysine 40. Rho-associated kinase Rock1 is an upstream regulator that modulates key properties of the cytoplasmic cytoskeleton. Our research shows that Rock1 concentrations were reduced significantly in senescent cells, and we revealed a mechanistic link between microtubule stabilization and Rock1 depletion. Thus, Rock1 overexpression partially restored the cold sensitivity of microtubules in cells undergoing senescence. Additional components relevant to microtubules were affected by senescence. Specifically, we uncovered the senescence-related loss of the microtubule nucleating protein γ-tubulin and aberrant formation of γ-tubulin foci. Concomitant with the alterations of microtubule and actin filaments, senescent cells displayed functional changes. In particular, cell migration was impaired significantly in senescent cells. Taken together, our study identified new senescence-associated deficiencies of the microtubule and actin cytoskeleton, provided insights into the underlying molecular mechanisms and demonstrated functional consequences that are important to the physiology and function of renal epithelial cells.

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Acknowledgements

This work was supported by Grants from NSERC (Natural Sciences and Engineering Research Council of Canada) to US and JFP. We thank Dr. M. Lora for performing the flow cytometry, and Drs. G. Brouhard (McGill University) and G. Gomez (University of Queensland, St. Lucia, Brisbane) for their generous gift of reagents.

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Authors and Affiliations

  1. Department of Physiology, McGill University, Montreal, Canada

    Ossama Moujaber, Francine Fishbein, Nawal Omran, Yue Liang & Ursula Stochaj

  2. Department of Rheumatology, McGill University, Montreal, Canada

    Inés Colmegna

  3. Department of Anatomy and Cell Biology, McGill University, Montreal, Canada

    John F. Presley

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  1. Ossama Moujaber
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Moujaber, O., Fishbein, F., Omran, N. et al. Cellular senescence is associated with reorganization of the microtubule cytoskeleton. Cell. Mol. Life Sci. 76, 1169–1183 (2019). https://doi.org/10.1007/s00018-018-2999-1

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