Microtubules tune mechanosensitive cell responses

Abstract

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 .

Using Polyacrylamide Hydrogels to Model Physiological Aortic Stiffness Reveals that Microtubules Are Critical Regulators of Isolated Smooth Muscle Cell Morphology and Contractility

“…Much is known about the synergistic nature of microtubules and actomyosin activity. Indeed, non-muscle myosin II has been shown to suppress microtubule growth in order to stabilise cell morphology ( Sato et al, 2020 ), whilst microtubule acetylation has been found to regulate actomyosin-derived force generation ( Joo and Yamada, 2014 ; Seetharaman et al, 2021 ). Actomyosin and microtubule cross-talk also regulates morphology during differentiation and cell migration in a variety of cell types ( Akhshi et al, 2014 ; Wu and Bezanilla, 2018 ; Seetharaman and Etienne-Manneville, 2020 ), suggesting that communication between these mechanical networks is fundamentally important in determining VSMC morphology.…”

Microtubules restrict F-actin polymerization to the immune synapse via GEF-H1 to maintain polarity in lymphocytes

“…Indeed, we observed that global activation of GEF-H1-RhoA axis induced actin polymerization outside of the synapse, independently of myosin II activity. Interestingly, it was recently shown that microtubules were acetylated in the vicinity of the centrosome upon immune synapse formation, resulting in the local release and activation of GEF-H1 (27, 30). Our results suggest that GEF-H1 might activate RhoA to trigger downstream formin-dependent actin nucleation at the immune synapse exclusively.…”

“…Our results suggest that GEF-H1 might activate RhoA to trigger downstream formin-dependent actin nucleation at the immune synapse exclusively. In this model, RhoA would remain inactive in the rest of the cell, most likely due to GEF-H1 trapping on microtubules deacetylated by HDAC6 (30, 31). We suggest that this “local activation” of GEF-H1 and “global inhibition” by trapping is a reminiscent of the Local Excitation Global Inhibition model, described in amoeba, where symmetry breaking arises from a local positive feedback (PIP3 that promotes F-actin polymerization) combined to a globally active diffusible inhibitory signal (PTEN, a PIP3 phosphatase) (32–34).…”

Viscoelasticity, Like Forces, Plays a Role in Mechanotransduction

“…Forces from the cellular environment are usually encountered primarily at the surface of the cell, where the force-generating cytoskeleton can also apply stresses as it comes into contact with various mechanical conditions. The adhesion complexes that connect cells to ambient tissues by focal adhesions and to other cells by adherens junctions have consequently been found to be key hubs in the transmission of forces ( Leckband and de Rooij, 2014 ; Seetharaman et al, 2021 ; Sun et al, 2016 ). There are, however, a much wider spectrum of mechanosensors inherent in cells, comprising several structurally diverse families of force-sensitive ion channels ( Kefauver et al, 2020 ) and receptors for biochemical ligands that react in a direct manner to force, such as notch ( Stassen et al, 2020 ) and plexin ( Mehta et al, 2020 ).…”