by Keyword: Keratins
Kechagia, Z, Sáez, P, Gómez-González, M, Canales, B, Viswanadha, S, Zamarbide, M, Andreu, I, Koorman, T, Beedle, AEM, Elosegui-Artola, A, Derksen, PWB, Trepat, X, Arroyo, M, Roca-Cusachs, P, (2023). The laminin-keratin link shields the nucleus from mechanical deformation and signalling Nature Materials 22, 1409-1420 
The mechanical properties of the extracellular matrix dictate tissue behaviour. In epithelial tissues, laminin is a very abundant extracellular matrix 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 β4 increases nuclear YAP ratios in a rigidity-dependent manner without affecting the cell forces or focal adhesions. By combining mechanical perturbations and mathematical modelling, we show that β4 integrins establish a mechanical linkage between the substrate and keratin cytoskeleton, which stiffens the network and shields the nucleus from actomyosin-mediated mechanical deformation. In turn, this affects the nuclear YAP mechanoresponses, chromatin methylation and cell invasion in three dimensions. Our results demonstrate a mechanism by which tissues can regulate their sensitivity to mechanical signals.© 2023. The Author(s).
JTD Keywords: actin, cell migration, filaments, force transmission, localization, membrane, motility, proteins, yap, Cell adhesion, Cytoskeleton, Extracellular matrix, Fibronectins, Integrin alpha-6-beta-4, Integrins, Keratins, Laminin
