αTAT1 defines a microtubule mechanosensing axis that drives fibroblast durotaxis and fibrosis across organs
Durotaxis, the directed migration of cells along gradients of extracellular stiffness, drives tissue fibrosis by recruiting fibroblasts to stiffened injury sites where hey differentiate into myofibroblasts and deposit scar tissue. While actin cytoskeletal tension and focal adhesion dynamics have been implicated in this process, the contribution of microtubules to cellular mechanosensing and durotaxis has remained undefined. Here, we uncover TAT1-mediated microtubule acetylation as a master regulator of fibroblast mechanosensing and stiffness-directed durotaxis. By catalyzing -tubulin K40 acetylation, TAT1 confers the structural flexibility required for directional microtubule alignment and persistent polarity along stiffness gradients, enabling fibroblasts to sense mechanical cues and initiate profibrotic programs. Loss of TAT1 abolishes K40 acetylation, disrupts focal adhesion FAK signaling, and suppresses YAP nuclear localization, thereby uncoupling extracellular matrix stiffness from downstream mechanotransduction. Global or fibroblast-specific deletion of TAT1 markedly reduces fibroblast durotaxis and myofibroblast accumulation, and protects mice from lung, dermal, and kidney fibrosis in experimental models, without affecting inflammation or vascular integrity. Together, our findings define TAT1-dependent microtubule mechanosensing as a central cytoskeletal pathway coupling fibroblast mechanobiology to organ fibrosis in vivo, positioning the TAT1 catalytic domain as a novel mechano-therapeutic target in fibrotic disease.