Mechanotransduction is a process by which cells sense the mechanical properties of their surrounding environment and adapt accordingly to perform cellular functions such as adhesion, migration and differentiation. Integrin-mediated focal adhesions are major sites of mechanotransduction and their connection with the actomyosin network is crucial for mechanosensing as well as the generation and transmission of forces onto the substrate. Despite having emerged as major regulators of cell adhesion and migration, the contribution of microtubules to mechanotransduction still remains elusive. Here, we show that actomyosin-dependent mechanosensing of substrate rigidity controls microtubule acetylation, a tubulin post-translational modification, by promoting the recruitment of the alpha-tubulin acetyl transferase (αTAT1) to focal adhesions. Microtubule acetylation, in turn, promotes GEF-H1 mediated RhoA activation, actomyosin contractility and traction forces. Our results reveal a fundamental crosstalk between microtubules and actin in mechanotransduction, which contributes to mechanosensitive cell adhesion and migration. MainCells sense the physical properties of their environment, translate them into biochemical signals and adapt their behaviour accordingly. This process known as mechanotransduction is crucial during development as well as in the adult during physiological and pathological conditions such as cell migration, wound healing and cancer 1,2 . Integrin-mediated focal adhesions (FAs) sense the matrix rigidity, control the generation of actomyosin-dependent forces and the transmission of these traction forces onto the substrate, as well as contribute to mechanosensitive cell responses such as migration 3,4 . In addition to the actin cytoskeleton, microtubules are also key regulators of 2D and 3D cell migration [5][6][7][8] . Several studies have demonstrated the role of the actomyosin cytoskeleton and FAs in mechanotransduction, however, very little is known about microtubules in this context. In this study, we used astrocytes, whose migration 2 | P a g e .

The E3 ubiquitin ligase Neuralized is shown to interact with a subset of the Stardust isoforms to regulate the endocytosis of the apical protein Crumbs and thereby promote epithelial remodeling during Drosophila development.