Microtubule acetylation but not detyrosination promotes focal adhesion dynamics and astrocyte migration

Abstract

Microtubules play a crucial role in mesenchymal migration by controlling cell polarity and the turnover of cell adhesive structures on the extracellular matrix. The polarized functions of microtubules imply that microtubules are locally regulated. Here, we investigated the regulation and role of two major tubulin post-translational modifications, acetylation and detyrosination, which have been associated with stable microtubules. Using primary astrocytes in a wound healing assay, we show that these tubulin modifications are independently regulated during cell polarization and differently affect cell migration. In contrast to microtubule detyrosination, αTAT1 (ATAT1)-mediated microtubule acetylation increases in the vicinity of focal adhesions and promotes cell migration. We further demonstrate that αTAT1 increases focal adhesion turnover by promoting Rab6-positive vesicle fusion at focal adhesions. Our results highlight the specificity of microtubule posttranslational modifications and bring new insight into the regulatory functions of tubulin acetylation. This article has an associated First Person interview with the first author of the paper.

Microtubules at focal adhesions – a double-edged sword

“…Furthermore, a proportion of these microtubules grow and bend to reach down towards the basal cell cortex, where they remain anchored (Etienne- Manneville et al, 2005). Also in this case, our group was able to show that microtubules run along FAs, without directly contacting them (Bance et al, 2019) (Fig. 1A,B).…”

“…How microtubule stability, as characterised by microtubule detyrosination or acetylation, is controlled remains unclear. In fact, our recent observations indicate that acetylation and detyrosination are regulated independently and may have different roles that are possibly unrelated to microtubule stability (Bance et al, 2019).…”

“…This interaction between Rab6, Rab8 and ELKS is key for the docking and fusion of vesicles at cortical adhesion sites to promote FA turnover. We also recently demonstrated a potential role for microtubule acetylation in controlling FA dynamics in astrocytes, as αTAT1, the enzyme responsible for microtubule acetylation, promotes Rab6mediated vesicular fusion at FAs, which regulates FA turnover and astrocyte migration (Bance et al, 2019). While it is easy to speculate that microtubules play a key role in delivering integrins and possible membrane-associated partners to FAs, their involvement in the precise control of vesicle delivery remains unclear.…”

The Tubulin Code in Mitosis and Cancer

“…While HDAC6 expression and activity was proposed to promote cell migration [12,126,[136][137][138], the opposite effect was observed after the loss of αTat1 or mutation of the α-tubulin lysine 40 (K40R) [99,137,139,140]. The establishment of cell adhesion to the substrate also has implications for cell motility, and the loss of either HDAC6 or αTat1 leads to an increased focal adhesion area and number, respectively, as well as decreased dynamics [137,141]. However, other works reported that loss of αTat1 leads to a decrease in focal adhesion number [122].…”

“…However, other works reported that loss of αTat1 leads to a decrease in focal adhesion number [122]. The basis for this discrepancy remains unclear, but it is likely associated with different experimental set ups: one study investigated the role of αTat1 in wound-induced migrating cells [137], while the other used normally growing cells were used [122], raising the possibility that αTat1 promotes focal adhesion dynamics specifically during cell migration.…”