Microtubules tune mechanosensitive cell responses
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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 for 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 talin- and actomyosin-dependent mechanosensing of substrate rigidity controls microtubule acetylation (a tubulin post-translational modification) by promoting the recruitment of α-tubulin acetyltransferase 1 (αTAT1) to focal adhesions. Microtubule acetylation tunes the mechanosensitivity of focal adhesions and Yes-associated protein (YAP) translocation. Microtubule acetylation, in turn, promotes the release of the guanine nucleotide exchange factor GEF-H1 from microtubules to activate RhoA, actomyosin contractility and traction forces. Our results reveal a fundamental crosstalk between microtubules and actin in mechanotransduction that contributes to mechanosensitive cell adhesion and migration.
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GFP-GEF-H1 bound along most microtubules in U2OS cells.
“GFP-GEF-H1 bound along most microtubules in U2OS cells”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [32]
The paper reports that GEF-H1 associates with microtubules in astrocytes: approximately 42% was microtubule-localized in controls and 60% after αTAT1 depletion (passage labeled Abstract; Fig. 4E–F). It does not establish that GFP-GEF-H1 bound along most microtubules in U2OS cells; the reported percentages describe GEF-H1 localization, not the proportion of microtubules bound. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGFP-GEF-H1 was barely detected on acetylated microtubules in U2OS cells.
“but was barely detected on acetylated microtubules (Fig. 3a, yellow dashed line, and Fig. 3c)”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [32]
The passage labeled Abstract (page unavailable) says microtubule acetylation promotes GEF-H1 release from microtubules, supporting the direction of the claim. It reports GEF-H1 localization in astrocytes, however, not barely detectable GFP-GEF-H1 on acetylated microtubules in U2OS cells; searches for those specific terms found no such result. (LLM, conf=0.82)
Experimental — accuracy not yet measuredLocal stabilization and expansion of microtubules near focal adhesions can potentially trigger GEF-H1 release and RhoA-dependent focal adhesion disassembly during cell movement.
“Furthermore, local stabilization and expansion of microtubules in the vicinity of focal adhesions 32,74 can potentially trigger GEF-H1 release and RhoA-dependent focal adhesion disassembly during cell movement.”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [32]
The paper reports that growing microtubule ends occur near focal adhesions in migrating cells, and that microtubule acetylation promotes GEF-H1 release and RhoA activation (sections labelled Abstract; pages unavailable). It also reports altered focal-adhesion dynamics, but does not establish that local microtubule stabilization and expansion trigger RhoA-dependent focal-adhesion disassembly. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBoth pharmacological and genetic HDAC6 loss increase actomyosin contractility, consistent with a lagged, acetylation‐dependent effect on the actomyosin cytoskeleton.
“Together, these data indicate that both pharmacological and genetic HDAC6 loss increase actomyosin contractility, consistent with a lagged, acetylation‐dependent effect on the actomyosin cytoskeleton [21].”
From Paclitaxel induces <scp>NM2</scp> ‐dependent cellular contraction through <scp>GEF</scp> ‐ <scp>H1</scp> dissociation from microtubules and <scp>RhoA</scp> / <scp>ROCK</scp> activation in cancer cells (2026) · cites this paper as [21]
The traction-force passage (labelled Abstract in our copy; page unavailable) reports that Tubacin, an HDAC6 inhibitor, increased traction forces in astrocytes. The Additional information identifies the genetic knockdown as targeting αTAT1, not HDAC6. The cited paper supports an acetylation-dependent link to actomyosin contractility, but does not establish genetic HDAC6 loss or a lagged effect. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe kinetics of GEF-H1 dissociation from microtubules induced by PTXL were much faster than those induced by inhibitors of HDAC6.
“Importantly, the kinetics of GEF‐H1 dissociation from microtubules induced by PTXL were much faster than those induced by inhibitors of HDAC6 [21]”
From Paclitaxel induces <scp>NM2</scp> ‐dependent cellular contraction through <scp>GEF</scp> ‐ <scp>H1</scp> dissociation from microtubules and <scp>RhoA</scp> / <scp>ROCK</scp> activation in cancer cells (2026) · cites this paper as [21]
The passage indexed under “Abstract” (page unavailable) reports that Tubacin treatment released GEF-H1 from microtubules into the cytosol. The Cell treatment section (page unavailable) identifies Tubacin as a treatment, but our copy does not report PTXL-induced release or compare the kinetics of PTXL and HDAC6 inhibitors (searched: PTXL, paclitaxel, and GEF-H1 dissociation kinetics). (LLM, conf=0.85)
Experimental — accuracy not yet measured
GEF-H1 avoids acetylated microtubules.
“Previous studies have suggested that GEF-H1 avoids acetylated microtubules 32,33 .”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [32]
In cells, GEF-H1 avoids acetylated, stable microtubules.
“In cells, GEF-H1 avoids acetylated, stable microtubules 32,33 , probably because their lattices are expanded 39,53 and are thus more similar in conformation to paclitaxel- and GMPCPP-stabilized microtubules.”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [32]
Acetylation of Lys40 in α-tubulin facilitates GEFH1 release and activation of the RhoA pathway.
“acetylation of Lys40 in α-tubulin facilitates GEFH1 release and activation of the RhoA pathway,13”
From Structural basis of microtubule-mediated signal transduction (2026) · cites this paper as [13]
Microtubule acetylation releases GEF-H1 from microtubules, thereby promoting actomyosin contractility.
“A recent study proposed that the mechanosensitive acetylation of microtubules releases GEF‐H1 from microtubules, thereby promoting actomyosin contractility [21].”
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References 60 · Cited by 210
Research works printed but not linked: 37
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- Authors
- Seetharaman, S., Vianay, B., Roca, V., Farrugia, A. J., De Pascalis, C., Boëda, B., Dingli, F., Loew, D., Vassilopoulos, S., Bershadsky, A., Théry, M., & Etienne-Manneville, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- National University of Singapore (SG)
- Université Paris Sciences et Lettres (FR)
- Inserm (FR)
- ORCID
- Venue
- Nature Materials
- Published
- 2021-10-18
- Volume
- 21
- Issue
- 3
- Pages
- 366-377
- ISSN
- 1476-1122 (ISSN-L)
- 1476-4660
- OpenAlex
- W3205850006
- Cited by
- 210
- References
- 60
- Citations by year
- 2026: 36 · 2025: 64 · 2024: 45 · 2023: 34 · 2022: 26 · 2021: 4 · 2020: 1
- FWCI
- 14.23
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Materials (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion, cc-by-nc)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- mechanotransduction, microtubules, microtubule acetylation, focal adhesions, integrins, talin, actomyosin contractility, YAP, GEF-H1, RhoA activation, substrate stiffness, cell adhesion, cell migration, traction force
- MeSH terms
- Cell Adhesion, Actin Cytoskeleton, Microtubules, Tubulin, Focal Adhesions, Mechanotransduction, Cellular
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