Interplay between Extracellular Matrix Stiffness and JAM-A Regulates Mechanical Load on ZO-1 and Tight Junction Assembly.

Cell Reports
Alexis J HaasKarl Matter

Abstract

Tight-junction-regulated actomyosin activity determines epithelial and endothelial tension on adherens junctions and drives morphogenetic processes; however, whether or not tight junctions themselves are under tensile stress is not clear. Here, we use a tension sensor based on ZO-1, a scaffolding protein that links the junctional membrane to the cytoskeleton, to determine if tight junctions carry a mechanical load. Our data indicate that ZO-1 is under mechanical tension and that forces acting on ZO-1 are regulated by extracellular matrix (ECM) stiffness and the junctional adhesion molecule JAM-A. JAM-A depletion stimulates junctional recruitment of p114RhoGEF/ARHGEF18, mechanical tension on ZO-1, and traction forces at focal adhesions. p114RhoGEF is required for activation of junctional actomyosin activity and tight junction integrity on stiff but not soft ECM. Thus, junctional ZO-1 bears a mechanical load, and junction assembly is regulated by interplay between the physical properties of the ECM and adhesion-regulated signaling at tight junctions.

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Citations

Sep 7, 2020·Trends in Cell Biology·Tetsuhisa Otani, Mikio Furuse
Jun 14, 2021·European Biophysics Journal : EBJ·Ilaria TortorellaFrancesco Morena
Jul 25, 2021·International Journal of Molecular Sciences·Ashley MonacoKurt Amsler
Sep 29, 2021·The Journal of Cell Biology·Chiara CamilloGuido Serini

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Methods Mentioned

BETA
FRET
confocal microscopy
transfection
biosensor
nucleotide exchange
PCR

Key Resources (RRID) Mentioned

Addgene_26021

Software Mentioned

Nikon
Fiji
Leica
MATLAB
JMP Pro
Adobe Photoshop
Leica FRET
ImageJ
Analyze Particle

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