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

Author (s): Kechagia, Z.; Sáez, P.; Gómez-González, M.; Canales, B.; Viswanadha, S.; Zamarbide, M.; Andreu, I.; Koorman, T.; Beedle, A.E.M.; Elosegui-Artola, A.; Derksen, P.W.B.; Trepat, X.; Arroyo M.; Roca-Cusachs P.
Journal: Nature Materials

Date: 2023

Abstract:
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.

Journal paper (from the publisher)