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bioRxiv · 10.1101/2022.03.01.482474

The laminin-keratin link shields the nucleus from mechanical deformation and signalling

Kechagia, Z.·Saez, P.·Gomez-Gonzalez, M.·Zamarbide, M.·Andreu, I.·Koorman, T.·Beedle, A. E. M.·Derksen, P. W. B.·Trepat, X.·Arroyo, M.·Roca-Cusachs, P.
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Abstract

The mechanical properties of the extracellular matrix (ECM) dictate tissue behaviour. In epithelial tissues, laminin is both a very abundant ECM component, and a key supporting element. Here we show that laminin hinders the mechanoresponses of breast epithelial cells by shielding the nucleus from mechanical deformation. Coating substrates with laminin-111, unlike fibronectin or collagen I, impairs cell response to substrate rigidity, and YAP nuclear localization. Blocking the laminin-specific integrin {beta}4 increases nuclear YAP ratios in a rigidity dependent manner, without affecting cell forces or focal adhesions. By combining mechanical perturbations and mathematical modelling, we show that {beta}4 integrins establish a mechanical linkage between the substrate and the keratin cytoskeleton, which stiffens the network and shields the nucleus from actomyosin-mediated mechanical deformation. In turn, this affects nuclear YAP mechanoresponses and chromatin methylation. Our results demonstrate a mechanism by which tissues can regulate their sensitivity to mechanical signals.

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Kechagia, Z., Saez, P., Gomez-Gonzalez, M., Zamarbide, M., Andreu, I., Koorman, T., Beedle, A. E. M., Derksen, P. W. B., Trepat, X., Arroyo, M., Roca-Cusachs, P.. 2022-03-01. The laminin-keratin link shields the nucleus from mechanical deformation and signalling. https://doi.org/10.1101/2022.03.01.482474

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