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

Zanetta Kechagia, Pablo Sáez, Manuel Gómez-González, Brenda Canales, Srivatsava Viswanadha, Martín Zamarbide, Ion Andreu, Thijs Koorman, Amy E. M. Beedle, Alberto Elosegui-Artola, Patrick W. B. Derksen, Xavier Trepat, Marino Arroyo, Pere Roca-Cusachs

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1409-1420
Number of pages12
JournalNATURE MATERIALS
Volume22
Issue number11
Early online date14 Sept 2023
DOIs
Publication statusPublished - 1 Nov 2023

Fingerprint

Dive into the research topics of 'The laminin–keratin link shields the nucleus from mechanical deformation and signalling'. Together they form a unique fingerprint.

Cite this