s41563-023-01657-3.pdf (5.81 MB)
The laminin-keratin link shields the nucleus from mechanical deformation and signalling.
journal contributionposted on 2023-11-09, 14:12 authored by Zanetta Kechagia, Pablo Sáez, Manuel Gómez-González, Brenda Canales, Srivatsava Viswanadha, Martín Zamarbide, Ion Andreu, Thijs Koorman, Amy EM Beedle, Alberto Elosegui-Artola, Patrick WB Derksen, Xavier Trepat, Marino Arroyo, Pere Roca-Cusachs
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.