TY - JOUR T1 - The laminin-keratin link shields the nucleus from mechanical deformation and signalling JF - bioRxiv DO - 10.1101/2022.03.01.482474 SP - 2022.03.01.482474 AU - Zanetta Kechagia AU - Pablo Sáez AU - Manuel Gómez-González AU - Martín Zamarbide AU - Ion Andreu AU - Thijs Koorman AU - Amy E.M. Beedle AU - Patrick W.B. Derksen AU - Xavier Trepat AU - Marino Arroyo AU - Pere Roca-Cusachs Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/03/01/2022.03.01.482474.abstract N2 - 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 β4 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 β4 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.Competing Interest StatementThe authors have declared no competing interest. ER -