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Review
. 2023 Apr 6;12(4):561.
doi: 10.3390/biology12040561.

Tubulin Post-Translational Modifications: The Elusive Roles of Acetylation

Bruno Carmona  1   2 , H Susana Marinho  3 , Catarina Lopes Matos  1 , Sofia Nolasco  2   4 , Helena Soares  1   2
Affiliations
Review

Tubulin Post-Translational Modifications: The Elusive Roles of Acetylation

Bruno Carmona et al. Biology (Basel). .

Abstract

Microtubules (MTs), dynamic polymers of α/β-tubulin heterodimers found in all eukaryotes, are involved in cytoplasm spatial organization, intracellular transport, cell polarity, migration and division, and in cilia biology. MTs functional diversity depends on the differential expression of distinct tubulin isotypes and is amplified by a vast number of different post-translational modifications (PTMs). The addition/removal of PTMs to α- or β-tubulins is catalyzed by specific enzymes and allows combinatory patterns largely enriching the distinct biochemical and biophysical properties of MTs, creating a code read by distinct proteins, including microtubule-associated proteins (MAPs), which allow cellular responses. This review is focused on tubulin-acetylation, whose cellular roles continue to generate debate. We travel through the experimental data pointing to α-tubulin Lys40 acetylation role as being a MT stabilizer and a typical PTM of long lived MTs, to the most recent data, suggesting that Lys40 acetylation enhances MT flexibility and alters the mechanical properties of MTs, preventing MTs from mechanical aging characterized by structural damage. Additionally, we discuss the regulation of tubulin acetyltransferases/desacetylases and their impacts on cell physiology. Finally, we analyze how changes in MT acetylation levels have been found to be a general response to stress and how they are associated with several human pathologies.

Keywords: HDAC6; Lys40; SIRT2; acetylation; microtubule-associated proteins; microtubule-mechanical properties; microtubules; post-translational modifications; tubulin; αTAT1.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Microtubule structure, dynamics, and tubulin folding and recycling pathways. To originate MTs, tubulin heterodimers interact head-to-tail, arranging in linear protofilaments. The lateral association of the protofilaments, in general, 13 protofilaments, creates the hollow cylindrical structure of the MT with about 25 nm of diameter. Since tubulin heterodimers are oriented inside the MT, this produces a structural polarity; one end of the MT always initiates with α-tubulin, whereas the other terminates with β-tubulin, which is reflected in the dynamic behavior of the polymer with the two ends of a MT displaying different rates of polymerization, a faster-growing end (where β-tubulin is exposed; plus end), and a slower-growing end (where the α-tubulin is ex-posed; minus end). MTs polymerize from soluble tubulin heterodimers bound to guanosine triphosphate (GTP). After incorporation in the polymer, the β-tubulin GTPase activity is activated, GTP is hydrolyzed to guanosine diphosphate (GDP), and the energy from that hydrolysis is assumed to induce conformational changes in tubulin, reducing the stability of the MT lattice (for review [12]). In growing MTs, most heterodimers in the lattice are bound to GDP. However, whenever a MT maintains a cap of GTP tubulin heterodimers at the tip, the entire polymer will be stabilized (the GTP cap model), and the MT grows. On the contrary, if the tip of the MT accumulates a critical number or density of GDP-tubulins, the MT lattice will become unstable, and the MT will transition to a depolymerization state, rapidly shrinking its length (a process designated as “catastrophe”). MTs show stochastic transitions between periods of shrinkage (catastrophe) and growth (rescue) in a process designated “dynamic instability”. A schematic representation of the tubulin folding and native dimer disassembly pathways is also shown. The CCT (cytosolic chaperonin-containing TCP1) captures tubulin folding intermediates, with important native-like domain structures, either directly from ribosomes or from the hetero-hexameric chaperone prefoldin (for review [13]). α- and β-tubulin monomers released from CCT follow different pathways: α-tubulin is captured by cofactor B (TBCB) and β-tubulin by cofactor A (TBCA). Then, cofactors E (TBCE) and D (TBCD) capture α- and β-tubulin, respectively. Additionally, after TBCC binding, a supercomplex is formed. TBCC stimulates GTP hydrolysis by β-tubulin and the consequent release of α/β-tubulin-GDP heterodimers. Upon exchange of GDP by GTP, a functional α/β-tubulin dimer competent to polymerize into a MT is formed. Along with tubulin folding, tubulin cofactors assist tubulin heterodimer assembly/dissociation, as well as tubulin degradation. Tubulin heterodimers released from MTs can be dissociated by cofactors and recycled or degraded. TBCD and TBCE are capable of dissociating the tubulin heterodimer by themselves, but in the case of TBCE, its dissociation activity is highly increased by the presence of TBCB. In this process, the β-tubulin is retained by TBCD, whereas α-tubulin is stabilized by the complex TBCB/TBCE. TBCA mainly receives β-tubulin from the dissociation of pre-existing heterodimers instead of newly synthesized tubulins. Both pathways may lead to the tubulin monomer degradation through the ubiquitin-proteasome system by unknown mechanisms. By recycling the tubulin heterodimers, the TBCE/TBCB+TBCA system is crucial for controlling the critical concentration of free tubulin heterodimers and MT dynamics in the cells [14]. TBCD activity is regulated by Arl2, a small GTP (guanosine triphosphate) binding protein of the Arf family. The figure was inspired on [15,16].
Figure 2
Figure 2
Tubulin post-translational modifications. Specific groups of functionally distinct MT structures and their more common PTMs are highlighted (i.e., centrosome, cilia, and mitotic spindle). Specific tubulins amino acid residues or tubulin specific domains where PTMs occur are indicated. PTMs chemical structure are specified. Tubulin PTMs caused by association with specific proteins, such as SUMO and ubiquitin, as well as those originated by specific proteolysis (detyrosination and Δ2 and Δ3 tubulin) are also shown. For Glutamylation PTM, only the chemical structure corresponding to monoglutamylation is shown.
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