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

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.