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

Area of Science:

• Cell Biology
• Biophysics
• Biochemistry

Background:

• Epithelial and endothelial tension are regulated by actomyosin activity at adherens junctions, driving morphogenetic processes.
• The mechanical state of tight junctions themselves, particularly whether they bear tensile stress, remains unclear.

Purpose of the Study:

• To investigate whether tight junctions are under mechanical load.
• To determine the factors regulating tension on tight junction components.

Main Methods:

• Development and application of a tension sensor based on ZO-1 (Zonula Occludens 1), a protein linking the junctional membrane to the cytoskeleton.
• Analysis of the effects of extracellular matrix (ECM) stiffness and junctional adhesion molecule A (JAM-A) on ZO-1 tension.

Main Results:

• Data indicate that ZO-1 is under mechanical tension.
• Forces acting on ZO-1 are modulated by ECM stiffness and JAM-A.
• JAM-A depletion increases ZO-1 tension and focal adhesion traction forces, involving p114RhoGEF/ARHGEF18.
• p114RhoGEF is essential for actomyosin activity and tight junction integrity on stiff ECM.

Conclusions:

• Tight junctions, specifically the ZO-1 protein, bear a mechanical load.
• Tight junction assembly is regulated by the interplay between ECM physical properties and adhesion-mediated signaling pathways.