Abstract
Matrix stiffening sustains fibrosis by recruiting fibroblasts to stiff fibrotic areas through durotaxis. Once recruited, fibroblasts become mechanically activated and promote scar formation. Although actin-based mechanotransduction and focal adhesion signaling are well established, how microtubules contribute to stiffness sensing and fibroblast activation in fibrosis remains incompletely understood. Here, we identify αTAT1-mediated microtubule acetylation as a key regulator of fibroblast mechanosensing, durotaxis, and profibrotic activation. Through α-tubulin K40 acetylation, αTAT1 promotes microtubule flexibility, directional alignment, and persistent polarity along stiffness gradients, thereby enabling stiffness-directed migration and fibroblast activation. Mechanistically, αTAT1-dependent microtubule acetylation regulates focal adhesion dynamics and downstream mechanotransduction. αTAT1 loss abolishes K40 acetylation, impairs FAK-mediated YAP/TAZ signaling, and prevents stiffness- and TGF-β–induced myofibroblast differentiation. Accordingly, global or fibroblast-specific Atat1 depletion reduces fibroblast durotaxis and the accumulation of profibrotic fibroblasts, protecting mice from lung, dermal, and kidney fibrosis without affecting inflammation or vascular integrity. Our findings establish αTAT1-dependent microtubule acetylation as a conserved mechanosensing pathway that links fibroblast durotaxis and activation to fibrosis across organs in vivo, and identify αTAT1 catalytic activity as a potential mechano-therapeutic target in fibrotic disease.
Authors
Alba Santos, Tamanna Islam, Maria-Anna Chrysovergi, Paula E. Grasberger, Vera Auernheimer, Taslim A. Al-Hilal, Santiago Lamas, David Lagares
Figure 5
αTAT1 deficiency protects mice from kidney fibrosis in the unilateral ureteral obstruction model.
