Tau-Mediated Cytoskeletal Stabilization Modulates Cell Mechanics and Vulnerability to Mechanical Strain

Abstract

Cells experience mechanical loading across a broad range of loading rates, from low strain rates that are generated during morphogenesis and tissue remodelling, to high and injurious strain rates that are sustained during ventilation-induced lung injury, blast-induced injury, and impact-induced traumatic brain injury. Cell survival under high strain rate loading conditions depends on the ability of the cytoskeleton and plasma membrane to sustain mechanical load without permanent damage. The activity of different cytoskeletal and membrane regulatory proteins could therefore modulate cell susceptibility to injury, but the underlying mechanisms of injury at high strain rate are poorly understood. Tau is a microtubule-associated protein best known for its role in stabilizing microtubules in neurons and as a marker of neurodegenerative disease. Here, we investigated how Tau expression, phosphorylation, and microtubule binding modulates cell viscoelastic behaviour and membrane integrity during high strain-rate uniaxial stretch. We show that Tau expression and de-phosphorylation stabilize microtubules and causes increases in cell stiffness, suppresses cytoskeletal fluidity, and heightens susceptibility to stretch-induced membrane poration. Interestingly, we also find that these effects cannot be explained by microtubule stabilization by Tau alone. Actin architecture acts as a key determinant of injury vulnerability at high strain rate, highlighting the importance of cytoskeletal fluidity and microtubule-actin crosstalk for rapid force dissipation. Significance StatementCells must rapidly adapt to mechanical stress during high strain rate deformation. This study shows that Tau, a microtubule-associated protein, modulates cellular mechanics by increasing stiffness, decreasing viscoelastic fluidity, and enhancing susceptibility to membrane poration under rapid stretch. While Tau-mediated microtubule stabilization contributes to these effects, actin architecture and microtubule-actin crosstalk are also critical determinants of injury vulnerability in Tau-expressing cells.