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Tubulin Posttranslational Modifications and Emerging Links to Human Disease

2018; Cell Press; Volume: 173; Issue: 6 Linguagem: Inglês

10.1016/j.cell.2018.05.018

1097-4172

Maria M. Magiera, Puja Singh, Sudarshan Gadadhar, Carsten Janke,

Epigenetics and DNA Methylation

Tubulin posttranslational modifications are currently emerging as important regulators of the microtubule cytoskeleton and thus have a strong potential to be implicated in a number of disorders. Here, we review the latest advances in understanding the physiological roles of tubulin modifications and their links to a variety of pathologies. Tubulin posttranslational modifications are currently emerging as important regulators of the microtubule cytoskeleton and thus have a strong potential to be implicated in a number of disorders. Here, we review the latest advances in understanding the physiological roles of tubulin modifications and their links to a variety of pathologies. Microtubules are one of the major components of the eukaryotic cytoskeleton and carry out a wide variety of key functions in virtually every cell. Microtubules are essential for cell polarity, cell shape, and intracellular transport. They build the mitotic and meiotic spindles, which are the key structures to divide chromosomes during cell division. Microtubules also assemble specialized structures such as axonemes, which are the backbones of cilia and flagella, centrioles, which are the core structures of centrosomes, and marginal bands in blood platelets. Notwithstanding the multiple structures they build, microtubule filaments are always assembled from highly conserved dimers of α- and β-tubulin, which raises the question of how they can adapt to so many different functions. In living cells, microtubules can interact with specific sets of microtubule-associated proteins (MAPs), including molecular motors and proteins that regulate microtubule dynamics. Thus, specialized microtubule functions depend to a large extent on which subset of MAPs they interact with. An emerging mechanism that can directly and most likely selectively control these interactions are tubulin posttranslational modifications. Posttranslational modifications of tubulin have been known for many decades; however, their functions have mostly remained elusive. This has changed over the last decade, when many of the enzymes involved in the catalysis of these modifications have been identified. Mechanistic studies revealed that these modifications can selectively control the functions of microtubules by either directly controlling their mechanical properties—and thus their stability—or by regulating the plethora of interactions with MAPs. These initial insights have underpinned the idea that tubulin modifications can form a kind of "tubulin code," which programs selected microtubules for specific intracellular functions (reviewed in Janke, 2014Janke C. The tubulin code: molecular components, readout mechanisms, and functions.J. Cell Biol. 2014; 206: 461-472Crossref PubMed Scopus (361) Google Scholar, Song and Brady, 2015Song Y. Brady S.T. Post-translational modifications of tubulin: pathways to functional diversity of microtubules.Trends Cell Biol. 2015; 25: 125-136Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar; Magiera et al., 2018Magiera M.M. Singh P. Janke C. Functions of tubulin posttranslational modifications.Cell. 2018; 173 (this issue): 1552Abstract Full Text PDF PubMed Scopus (15) Google Scholar, this issue of Cell). Recently, the manipulation of tubulin-modifying enzymes in different model organisms has led to a significant advance in understanding the physiological contributions of these modifications and suggested links to pathologies. Moreover, the first direct links to human diseases have been identified with the discovery of mutations in genes encoding tubulin-modifying enzymes. Here, we review the current state of understanding of tubulin posttranslational modifications in mouse models and human pathologies (Figure 1). Most of the known tubulin modifications strongly accumulate at axonemes, the microtubule-based core structures of eukaryotic cilia and flagella. All functional data so far point to important roles of tubulin modifications in ciliary maintenance and function (Wloga et al., 2017Wloga D. Joachimiak E. Louka P. Gaertig J. Posttranslational Modifications of Tubulin and Cilia.Cold Spring Harb. Perspect. Biol. 2017; 9: a028159Crossref PubMed Scopus (72) Google Scholar). In humans, disorders of cilia can lead to a wide range of pathologies, which are commonly referred to as ciliopathies (Reiter and Leroux, 2017Reiter J.F. Leroux M.R. Genes and molecular pathways underpinning ciliopathies.Nat. Rev. Mol. Cell Biol. 2017; 18: 533-547Crossref PubMed Scopus (715) Google Scholar). These can be related to dysfunctions of motile cilia and flagella but also to defects of the non-motile, primary cilia. The beating of motile cilia and flagella is powered by axonemal dynein motors. Previous work identified tubulin polyglutamylation (addition of multiple glutamate residues to C-terminal tubulin tails; Magiera et al., 2018Magiera M.M. Singh P. Janke C. Functions of tubulin posttranslational modifications.Cell. 2018; 173 (this issue): 1552Abstract Full Text PDF PubMed Scopus (15) Google Scholar) as an important regulator of this beating, thus making it essential for ciliary function. Mutations in glutamylases (TTLL1, TTLL9) and deglutamylases (CCP1, CCP5) lead to aberrations in spermatogenesis and sperm motility in mice that result in male infertility (Konno et al., 2016Konno A. Ikegami K. Konishi Y. Yang H.-J. Abe M. Yamazaki M. Sakimura K. Yao I. Shiba K. Inaba K. Setou M. Ttll9-/- mice sperm flagella show shortening of doublet 7, reduction of doublet 5 polyglutamylation and a stall in beating.J. Cell Sci. 2016; 129: 2757-2766Crossref PubMed Scopus (28) Google Scholar, Mullen et al., 1976Mullen R.J. Eicher E.M. Sidman R.L. Purkinje cell degeneration, a new neurological mutation in the mouse.Proc. Natl. Acad. Sci. USA. 1976; 73: 208-212Crossref PubMed Scopus (455) Google Scholar, Vogel et al., 2010Vogel P. Hansen G. Fontenot G. Read R. Tubulin tyrosine ligase-like 1 deficiency results in chronic rhinosinusitis and abnormal development of spermatid flagella in mice.Vet. Pathol. 2010; 47: 703-712Crossref PubMed Scopus (58) Google Scholar, Wu et al., 2017Wu H.-Y. Wei P. Morgan J.I. Role of Cytosolic Carboxypeptidase 5 in Neuronal Survival and Spermatogenesis.Sci. Rep. 2017; 7: 41428Crossref PubMed Scopus (15) Google Scholar). Alterations in tubulin polyglutamylation also affect the beating of other types of motile cilia, such as ependymal cilia in the brain ventricle (Bosch Grau et al., 2013Bosch Grau M. Gonzalez Curto G. Rocha C. Magiera M.M. Marques Sousa P. Giordano T. Spassky N. Janke C. Tubulin glycylases and glutamylases have distinct functions in stabilization and motility of ependymal cilia.J. Cell Biol. 2013; 202: 441-451Crossref PubMed Scopus (65) Google Scholar) or airway cilia (Ikegami et al., 2010Ikegami K. Sato S. Nakamura K. Ostrowski L.E. Setou M. Tubulin polyglutamylation is essential for airway ciliary function through the regulation of beating asymmetry.Proc. Natl. Acad. Sci. USA. 2010; 107: 10490-10495Crossref PubMed Scopus (107) Google Scholar, Konno et al., 2016Konno A. Ikegami K. Konishi Y. Yang H.-J. Abe M. Yamazaki M. Sakimura K. Yao I. Shiba K. Inaba K. Setou M. Ttll9-/- mice sperm flagella show shortening of doublet 7, reduction of doublet 5 polyglutamylation and a stall in beating.J. Cell Sci. 2016; 129: 2757-2766Crossref PubMed Scopus (28) Google Scholar). While inactivation of the polyglutamylase TTLL1 leads to respiratory disorders in mice (Ikegami et al., 2010Ikegami K. Sato S. Nakamura K. Ostrowski L.E. Setou M. Tubulin polyglutamylation is essential for airway ciliary function through the regulation of beating asymmetry.Proc. Natl. Acad. Sci. USA. 2010; 107: 10490-10495Crossref PubMed Scopus (107) Google Scholar), no human disease directly linking aberrations of polyglutamylation to defects in motile cilia or sperm flagella has been identified so far. Non-motile or primary cilia are found on many human cell types where they fulfill essential functions as sensory organelles and signaling hubs. In a mouse model with a mutation in the deglutamylase CCP1, upregulated polyglutamylation leads to degeneration of photoreceptors in the retina. Photoreceptors contain a modified form of primary cilia—the connecting cilium, which may become dysfunctional due to hyperglutamylation—and cause these cells to degenerate (Marchena et al., 2011Marchena M. Lara J. Aijón J. Germain F. de la Villa P. Velasco A. The retina of the PCD/PCD mouse as a model of photoreceptor degeneration. A structural and functional study.Exp. Eye Res. 2011; 93: 607-617Crossref PubMed Scopus (12) Google Scholar). The importance of this mechanism for humans has been recently confirmed by the discovery of mutations in the tubulin deglutamylase CCP5 in human vision disorders (Astuti et al., 2016Astuti G.D.N. Arno G. Hull S. Pierrache L. Venselaar H. Carss K. Raymond F.L. Collin R.W.J. Faradz S.M.H. van den Born L.I. et al.Mutations in AGBL5, Encoding α-Tubulin Deglutamylase, Are Associated With Autosomal Recessive Retinitis Pigmentosa.Invest. Ophthalmol. Vis. Sci. 2016; 57: 6180-6187Crossref PubMed Scopus (15) Google Scholar, Branham et al., 2016Branham K. Matsui H. Biswas P. Guru A.A. Hicks M. Suk J.J. Li H. Jakubosky D. Long T. Telenti A. et al.Establishing the involvement of the novel gene AGBL5 in retinitis pigmentosa by whole genome sequencing.Physiol. Genomics. 2016; 48: 922-927Crossref PubMed Scopus (24) Google Scholar, Kastner et al., 2015Kastner S. Thiemann I.-J. Dekomien G. Petrasch-Parwez E. Schreiber S. Akkad D.A. Gerding W.M. Hoffjan S. Günes S. Günes S. et al.Exome Sequencing Reveals AGBL5 as Novel Candidate Gene and Additional Variants for Retinitis Pigmentosa in Five Turkish Families.Invest. Ophthalmol. Vis. Sci. 2015; 56: 8045-8053Crossref PubMed Scopus (25) Google Scholar). Glycylation (addition of multiple glycine residues to C-terminal tubulin tails, Magiera et al., 2018Magiera M.M. Singh P. Janke C. Functions of tubulin posttranslational modifications.Cell. 2018; 173 (this issue): 1552Abstract Full Text PDF PubMed Scopus (15) Google Scholar) is, in contrast to all other known tubulin modifications, predominantly found in cilia and flagella (Gadadhar et al., 2017Gadadhar S. Dadi H. Bodakuntla S. Schnitzler A. Bièche I. Rusconi F. Janke C. Tubulin glycylation controls primary cilia length.J. Cell Biol. 2017; 216: 2701-2713Crossref PubMed Scopus (44) Google Scholar, Wloga et al., 2017Wloga D. Joachimiak E. Louka P. Gaertig J. Posttranslational Modifications of Tubulin and Cilia.Cold Spring Harb. Perspect. Biol. 2017; 9: a028159Crossref PubMed Scopus (72) Google Scholar). Because of its specificity for cilia, glycylation is predestined to be a specific risk factor for ciliopathies. Tubulin glycylation is essential for the integrity of motile cilia in mouse ependymal cells (Bosch Grau et al., 2013Bosch Grau M. Gonzalez Curto G. Rocha C. Magiera M.M. Marques Sousa P. Giordano T. Spassky N. Janke C. Tubulin glycylases and glutamylases have distinct functions in stabilization and motility of ependymal cilia.J. Cell Biol. 2013; 202: 441-451Crossref PubMed Scopus (65) Google Scholar) and for the control of primary cilia length (Gadadhar et al., 2017Gadadhar S. Dadi H. Bodakuntla S. Schnitzler A. Bièche I. Rusconi F. Janke C. Tubulin glycylation controls primary cilia length.J. Cell Biol. 2017; 216: 2701-2713Crossref PubMed Scopus (44) Google Scholar). Absence of glycylation in photoreceptors leads to shortening of the connecting cilium of these cells, which is followed by retinal degeneration in mice (Bosch Grau et al., 2017Bosch Grau M. Masson C. Gadadhar S. Rocha C. Tort O. Marques Sousa P. Vacher S. Bieche I. Janke C. Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration.J. Cell Sci. 2017; 130: 938-949Crossref PubMed Scopus (40) Google Scholar). A rather unexpected link between glycylation and cancer was found in colorectal cancer. Knockout of the glycylase TTLL3 in mouse led to loss of primary cilia in colon and accelerated the proliferation of cancerous lesions. Strikingly, downregulation of TTLL3 expression was linked to colon cancer in human patients, thus confirming the relevance of this mechanism for the human disease (Rocha et al., 2014Rocha C. Papon L. Cacheux W. Marques Sousa P. Lascano V. Tort O. Giordano T. Vacher S. Lemmers B. Mariani P. et al.Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon.EMBO J. 2014; 33: 2247-2260Crossref PubMed Scopus (60) Google Scholar). Other tubulin modifications, such as detyrosination (removal of the ultimate gene-encoded tyrosine residue of α-tubulin), Δ2-tubulin (removal of the penultimate glutamate from detyrosinated α-tubulin; Johnson, 1998Johnson K.A. The axonemal microtubules of the Chlamydomonas flagellum differ in tubulin isoform content.J. Cell Sci. 1998; 111: 313-320Crossref PubMed Google Scholar), and acetylation of the luminal lysine-40 residue of α-tubulin (Wloga et al., 2017Wloga D. Joachimiak E. Louka P. Gaertig J. Posttranslational Modifications of Tubulin and Cilia.Cold Spring Harb. Perspect. Biol. 2017; 9: a028159Crossref PubMed Scopus (72) Google Scholar, Magiera et al., 2018Magiera M.M. Singh P. Janke C. Functions of tubulin posttranslational modifications.Cell. 2018; 173 (this issue): 1552Abstract Full Text PDF PubMed Scopus (15) Google Scholar) are also strongly enriched on axonemal microtubules of cilia and flagella. Among these, acetylation has been shown to affect sperm morphology and motility, as mice without the tubulin acetyl transferase αTAT1 are subfertile (Kalebic et al., 2013Kalebic N. Sorrentino S. Perlas E. Bolasco G. Martinez C. Heppenstall P.A. αTAT1 is the major α-tubulin acetyltransferase in mice.Nat. Commun. 2013; 4: 1962Crossref PubMed Scopus (139) Google Scholar). Considering that human sperm is more prone to qualitative and quantitative deficiencies than their mouse counterparts, mutations that lead to subfertility in mice could potentially cause male sterility in humans (Kherraf et al., 2017Kherraf Z.-E. Christou-Kent M. Karaouzene T. Amiri-Yekta A. Martinez G. Vargas A.S. Lambert E. Borel C. Dorphin B. Aknin-Seifer I. et al.SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes.EMBO Mol. Med. 2017; 9: 1132-1149Crossref PubMed Scopus (75) Google Scholar). Cytosolic microtubules are also subject to posttranslational modification. Neurons present an interesting case, as they are the only known cell type in which tubulin posttranslational modifications are strongly enriched on most cytosolic microtubules. The neuronal microtubule cytoskeleton is involved in neuronal differentiation and connectivity and plays a key role in intracellular transport over long distances. Polyglutamylation accumulates during neuronal differentiation and is therefore considered a potential key regulator of these different functions of neuronal microtubules. An important insight into the physiological role of polyglutamylation for neurons came with the discovery that a well-characterized mouse model for neurodegeneration, the Purkinje-cell degeneration (pcd) mouse (Mullen et al., 1976Mullen R.J. Eicher E.M. Sidman R.L. Purkinje cell degeneration, a new neurological mutation in the mouse.Proc. Natl. Acad. Sci. USA. 1976; 73: 208-212Crossref PubMed Scopus (455) Google Scholar), bears a mutation in the gene encoding a deglutamylase enzyme, CCP1. The mutation leads to excessive accumulation of tubulin polyglutamylation, specifically in regions of the nervous system that undergo degeneration (Rogowski et al., 2010Rogowski K. van Dijk J. Magiera M.M. Bosc C. Deloulme J.-C. Bosson A. Peris L. Gold N.D. Lacroix B. Bosch Grau M. et al.A family of protein-deglutamylating enzymes associated with neurodegeneration.Cell. 2010; 143: 564-578Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). The most emblematic neurons that degenerate in the pcd mouse are Purkinje cells in the cerebellum and Mitral cells in the olfactory bulb (Mullen et al., 1976Mullen R.J. Eicher E.M. Sidman R.L. Purkinje cell degeneration, a new neurological mutation in the mouse.Proc. Natl. Acad. Sci. USA. 1976; 73: 208-212Crossref PubMed Scopus (455) Google Scholar). The timing of the degeneration of these two neuronal populations is different, which could be related to their individual susceptibilities to the deleterious insults. The correlation between excessive polyglutamylation and neurodegeneration observed in pcd mice raises the possibility that many other neuron types could degenerate upon pathologically upregulated tubulin polyglutamylation. This could be induced either by mutations in one of the modifying enzymes or by defects in regulatory circuits that control the levels of modification. Thus far, little is known about the molecular mechanisms that are controlled by polyglutamylation in neurons. Initial observations suggested an important role in the regulation of axonal transport with an impact on synaptic transmission (Ikegami et al., 2007Ikegami K. Heier R.L. Taruishi M. Takagi H. Mukai M. Shimma S. Taira S. Hatanaka K. Morone N. Yao I. et al.Loss of alpha-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function.Proc. Natl. Acad. Sci. USA. 2007; 104: 3213-3218Crossref PubMed Scopus (181) Google Scholar, Maas et al., 2009Maas C. Belgardt D. Lee H.K. Heisler F.F. Lappe-Siefke C. Magiera M.M. van Dijk J. Hausrat T.J. Janke C. Kneussel M. Synaptic activation modifies microtubules underlying transport of postsynaptic cargo.Proc. Natl. Acad. Sci. USA. 2009; 106: 8731-8736Crossref PubMed Scopus (103) Google Scholar), and it is also likely that it affects microtubule dynamics via the regulation of the microtubule-severing enzyme spastin (Lacroix et al., 2010Lacroix B. van Dijk J. Gold N.D. Guizetti J. Aldrian-Herrada G. Rogowski K. Gerlich D.W. Janke C. Tubulin polyglutamylation stimulates spastin-mediated microtubule severing.J. Cell Biol. 2010; 189: 945-954Crossref PubMed Scopus (192) Google Scholar, Valenstein and Roll-Mecak, 2016Valenstein M.L. Roll-Mecak A. Graded Control of Microtubule Severing by Tubulin Glutamylation.Cell. 2016; 164: 911-921Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). Detyrosination and Δ2-tubulin are prominent modifications in neurons and found on all microtubules except those of the growth cone. Functional insight into the importance of these modifications came from tubulin-tyrosine ligase (TTL) knockout mice, which show strongly upregulated levels of both detyrosinated tubulin and Δ2-tubulin in the brain. TTL-knockout mice die perinatally due to massive defects in brain architecture, particularly in the cortico-thalamic loop (Erck et al., 2005Erck C. Peris L. Andrieux A. Meissirel C. Gruber A.D. Vernet M. Schweitzer A. Saoudi Y. Pointu H. Bosc C. et al.A vital role of tubulin-tyrosine-ligase for neuronal organization.Proc. Natl. Acad. Sci. USA. 2005; 102: 7853-7858Crossref PubMed Scopus (218) Google Scholar). The most likely reasons for these defects are aberrant timing and extent of neurite outgrowth (Erck et al., 2005Erck C. Peris L. Andrieux A. Meissirel C. Gruber A.D. Vernet M. Schweitzer A. Saoudi Y. Pointu H. Bosc C. et al.A vital role of tubulin-tyrosine-ligase for neuronal organization.Proc. Natl. Acad. Sci. USA. 2005; 102: 7853-7858Crossref PubMed Scopus (218) Google Scholar, Prota et al., 2013Prota A.E. Magiera M.M. Kuijpers M. Bargsten K. Frey D. Wieser M. Jaussi R. Hoogenraad C.C. Kammerer R.A. Janke C. Steinmetz M.O. Structural basis of tubulin tyrosination by tubulin tyrosine ligase.J. Cell Biol. 2013; 200: 259-270Crossref PubMed Scopus (150) Google Scholar). Milder alterations of this modification could be involved in neurodevelopmental disorders in humans; however, no such cases have been reported so far. The recent discovery of the enzymes catalyzing detyrosination (Aillaud et al., 2017Aillaud C. Bosc C. Peris L. Bosson A. Heemeryck P. Van Dijk J. Le Friec J. Boulan B. Vossier F. Sanman L.E. et al.Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation.Science. 2017; 358: 1448-1453Crossref PubMed Scopus (139) Google Scholar, Nieuwenhuis et al., 2017Nieuwenhuis J. Adamopoulos A. Bleijerveld O.B. Mazouzi A. Stickel E. Celie P. Altelaar M. Knipscheer P. Perrakis A. Blomen V.A. Brummelkamp T.R. Vasohibins encode tubulin detyrosinating activity.Science. 2017; 358: 1453-1456Crossref PubMed Scopus (122) Google Scholar) now allows a more thorough analysis of the enzymatic machinery that controls the detyrosination-tyrosination cycle and might thus point to disease links in humans. Acetylation is enriched on all neuronal microtubules. During neuronal development, the modification controls axon branching (Wei et al., 2017Wei D. Gao N. Li L. Zhu J.-X. Diao L. Huang J. Han Q.-J. Wang S. Xue H. Wang Q. et al.α-Tubulin Acetylation Restricts Axon Overbranching by Dampening Microtubule Plus-End Dynamics in Neurons.Cereb. Cortex. 2017; https://doi.org/10.1093/cercor/bhx1225Crossref PubMed Google Scholar) and plays a role in migration and morphological development of cortical neurons (Li et al., 2012Li L. Wei D. Wang Q. Pan J. Liu R. Zhang X. Bao L. MEC-17 deficiency leads to reduced α-tubulin acetylation and impaired migration of cortical neurons.J. Neurosci. 2012; 32: 12673-12683Crossref PubMed Scopus (59) Google Scholar). These functions could be explained by the recent finding that tubulin acetylation renders microtubules resistant to mechanical stress (Xu et al., 2017Xu Z. Schaedel L. Portran D. Aguilar A. Gaillard J. Marinkovich M.P. Théry M. Nachury M.V. Microtubules acquire resistance from mechanical breakage through intralumenal acetylation.Science. 2017; 356: 328-332Crossref PubMed Scopus (241) Google Scholar). However, given that acetylation is located in the inaccessible lumen of microtubules, the finding that this modification can also control axonal transport came as a surprise. Axonal transport defects have been linked to decreased tubulin acetylation in a range of neurodegenerative disorders, such as Huntington's disease (Dompierre et al., 2007Dompierre J.P. Godin J.D. Charrin B.C. Cordelières F.P. King S.J. Humbert S. Saudou F. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation.J. Neurosci. 2007; 27: 3571-3583Crossref PubMed Scopus (596) Google Scholar), Charcot-Marie-Tooth disease (d'Ydewalle et al., 2011d'Ydewalle C. Krishnan J. Chiheb D.M. Van Damme P. Irobi J. Kozikowski A.P. Vanden Berghe P. Timmerman V. Robberecht W. Van Den Bosch L. HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease.Nat. Med. 2011; 17: 968-974Crossref PubMed Scopus (343) Google Scholar, Kim et al., 2016Kim J.-Y. Woo S.-Y. Hong Y.B. Choi H. Kim J. Choi H. Mook-Jung I. Ha N. Kyung J. Koo S.K. et al.HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation.Stem Cells Int. 2016; 2016: 9475981Crossref PubMed Scopus (39) Google Scholar), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (Godena et al., 2014Godena V.K. Brookes-Hocking N. Moller A. Shaw G. Oswald M. Sancho R.M. Miller C.C.J. Whitworth A.J. De Vos K.J. Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations.Nat. Commun. 2014; 5: 5245Crossref PubMed Scopus (186) Google Scholar). In these studies, which used mouse models or neurons obtained from patient-derived pluripotent stem cells, chemical inhibition of the deacetylating enzyme HDAC6 was sufficient to restore normal tubulin acetylation levels, as well as normal axonal transport. To what extent acetylation alone is responsible for the observed transport defects remains to be verified, particularly because mice lacking tubulin acetyl transferase (ATAT1) merely showed defects in touch sensation but did not develop any of the expected degenerative phenotypes despite the complete absence of tubulin acetylation (Morley et al., 2016Morley S.J. Qi Y. Iovino L. Andolfi L. Guo D. Kalebic N. Castaldi L. Tischer C. Portulano C. Bolasco G. et al.Acetylated tubulin is essential for touch sensation in mice.eLife. 2016; 5: e20813Crossref PubMed Scopus (52) Google Scholar). Blood platelets are essential for the arrest of bleeding following injury, and their distinctive shape is maintained by a circular assembly of microtubules, the marginal band. Microtubules in the marginal band are rapidly reorganized during the process of platelet activation, which leads to blood clotting. The precise control of this peculiar microtubule assembly is thus an important factor in the function of platelets. Detyrosination, Δ2-tubulin, and acetylation have been detected on microtubules of marginal band (Diagouraga et al., 2014Diagouraga B. Grichine A. Fertin A. Wang J. Khochbin S. Sadoul K. Motor-driven marginal band coiling promotes cell shape change during platelet activation.J. Cell Biol. 2014; 204: 177-185Crossref PubMed Scopus (57) Google Scholar). Defects in tubulin acetylation affect the maturation of megakaryocytes (the precursors of platelets) and thus platelet formation (Iancu-Rubin et al., 2012Iancu-Rubin C. Gajzer D. Mosoyan G. Feller F. Mascarenhas J. Hoffman R. Panobinostat (LBH589)-induced acetylation of tubulin impairs megakaryocyte maturation and platelet formation.Exp. Hematol. 2012; 40: 564-574Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Tight control of acetylation and deacetylation events is further important during platelet spreading after activation (Sadoul et al., 2012Sadoul K. Wang J. Diagouraga B. Vitte A.-L. Buchou T. Rossini T. Polack B. Xi X. Matthias P. Khochbin S. HDAC6 controls the kinetics of platelet activation.Blood. 2012; 120: 4215-4218Crossref PubMed Scopus (49) Google Scholar). It is thus possible that defects in tubulin acetylation may play a role in human bleeding disorders. Tubulin detyrosination accumulates at early steps of muscle cell differentiation, while acetylation levels rise later in this process. It has recently been demonstrated that tubulin detyrosination affects mechanotransduction in muscle cells (Kerr et al., 2015Kerr J.P. Robison P. Shi G. Bogush A.I. Kempema A.M. Hexum J.K. Becerra N. Harki D.A. Martin S.S. Raiteri R. et al.Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle.Nat. Commun. 2015; 6: 8526Crossref PubMed Scopus (126) Google Scholar) and is important for load-bearing of buckling microtubules during cardiomyocyte contraction. Excess or diminished tubulin detyrosination changes the stiffness of the cardiomyocytes, thus leading to cardiac dysfunction. Upregulated tubulin detyrosination was found in patients diagnosed with hypertrophic and dilated cardiomyopathies (Robison et al., 2016Robison P. Caporizzo M.A. Ahmadzadeh H. Bogush A.I. Chen C.Y. Margulies K.B. Shenoy V.B. Prosser B.L. Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes.Science. 2016; 352: aaf0659Crossref PubMed Scopus (177) Google Scholar). These first clinical links indicate that alterations of the tyrosination-detyrosination balance could be a risk factor for heart failure and be more generally linked to muscle dysfunctions in a range of different diseases. Most of the known tubulin modifications have been detected on microtubules of the cell division machinery, such as mitotic and meiotic spindles, midbody microtubules, and particularly on centrioles, the microtubule-based core structures of the centrosomes. Tubulin modifications might control the precision of cell division; for instance, detyrosination, which impacts binding of a kinetochore-associated motor protein CENP-E, helps guide all chromosomes toward the metaphase plate in mitosis, and absence of this tubulin modification leads to misaligned chromosomes (Barisic et al., 2015Barisic M. Silva e Sousa R. Tripathy S.K. Magiera M.M. Zaytsev A.V. Pereira A.L. Janke C. Grishchuk E.L. Maiato H. Mitosis. Microtubule detyrosination guides chromosomes during mitosis.Science. 2015; 348: 799-803Crossref PubMed Scopus (156) Google Scholar). This deficit could lead to aneuploidy, a hallmark of cancer. There are several indications that deregulated detyrosination is indeed linked to cancer. Differential expression of TTL correlates with poor prognosis in neuroblastoma tumors (Kato et al., 2004Kato C. Miyazaki K. Nakagawa A. Ohira M. Nakamura Y. Ozaki T. Imai T. Nakagawara A. Low expression of human tubulin tyrosine ligase and suppressed tubulin tyrosination/detyrosination cycle are associated with impaired neuronal differentiation in neuroblastomas with poor prognosis.Int. J. Cancer. 2004; 112: 365-375Crossref PubMed Scopus (68) Google Scholar), and detyrosination of tubulin was particularly prominent in aggressive subtypes of breast cancer (Mialhe et al., 2001Mialhe A. Lafanechère L. Treilleux I. Peloux N. Dumontet C. Brémond A. Panh M.H. Payan R. Wehland J. Margolis R.L. Job D. Tubulin detyrosination is a frequent occurrence in breast cancers of poor prognosis.Cancer Res. 2001; 61: 5024-5027PubMed Google Scholar). Moreover, the recent discovery that vasohibins are the enzymes catalyzing detyrosination (Aillaud et al., 2017Aillaud C. Bosc C. Peris L. Bosson A. Heemeryck P. Van Dijk J. Le Friec J. Boulan B. Vossier F. Sanman L.E. et al.Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation.Science. 2017; 358: 1448-1453Crossref PubMed Scopus (139) Google Scholar, Nieuwenhuis et al., 2017Nieuwenhuis J. Adamopoulos A. Bleijerveld O.B. Mazouzi A. Stickel E. Celie P. Altelaar M. Knipscheer P. Perrakis A. Blomen V.A. Brummelkamp T.R. Vasohibins encode tubulin detyrosinating activity.Science. 2017; 358: 1453-1456Crossref PubMed Scopus (122) Google Scholar) provides new links between this tubulin modification and already-known associations between vasohibin dysfunctions and cancer (Du et al., 2017Du H. Zhao J. Hai L. Wu J. Yi H. Shi Y. The roles of vasohibin and its family members: Beyond angiogenesis modulators.Cancer Biol. Ther. 2017; 18: 827-832Crossref PubMed Scopus (19) Google Scholar). In female meiosis, detyrosinated microtubules are asymmetrically enriched on one half of the meiotic spindle, which drives non-Mendelian chromosome transmission in mouse oocytes (Akera et al., 2017Akera T. Chmatal L. Trimm E. Yang K. Aonbangkhen C. Chenoweth D.M. Janke C. Schultz R.M. Lampson M.A. Spindle asymmetry drives non-Mendelian chromosome segregation.Science. 2017; 358: 668-672Crossref PubMed Scopus (127) Google Scholar). This shows that tubulin modifications can impact inheritance and thus might affect the transmission of familial monogenic disorders; however, no implication in a human pathology has so far been described. Acetylation and polyglutamylation are both enriched on mitotic and meiotic spindle microtubules, midbody microtubules, and centrioles; however, their functional contribution is yet to be elucidated. Injection of anti-glutamylation antibodies into dividing cells compromises centrosome integrity (Bobinnec et al., 1998Bobinnec Y. Khodjakov A. Mir L.M. Rieder C.L. Eddé B. Bornens M. Centriole disassembly in vivo and its effect on centrosome structure and function in vertebrate cells.J. Cell Biol. 1998; 143: 1575-1589Crossref PubMed Scopus (302) Google Scholar), which suggests that the polyglutamylation of the centrioles is important for centrosome functions. Though no human disorder has been linked to tubulin modifications of centrioles, aberrations in these modifications might induce centrosome abnormalities, which are common hallmarks of cancer. Recent functional studies, most of them in mouse models, hint at a wide range of potential implications of tubulin posttranslational modifications in pathologies. Several predictions of disease-causing roles for tubulin modifications are now confirmed in human disorders, often with phenotypes highly similar to the ones observed in the mouse models (Figure 1). It is likely that the rapid advances in human genome profiling will uncover novel links between human pathologies and aberrant tubulin posttranslational modifications in the near future. Once these links are identified, it will be essential to determine how altered tubulin modifications contribute to the respective disease phenotypes. It will thus be necessary to further develop experimental systems that allow direct measures of the impact of tubulin modifications on microtubule properties and functions in vitro and in cell models. This task could be challenging, as most of the known tubulin modifications appear to have rather subtle biological effects. While this might be one of the central reasons tubulin modifications have often been overlooked as regulators of biological processes, it also makes these modifications perfect candidates for risk factors of late-onset or slow-developing disorders. Despite being dispensable for basic functions of cells and organisms, fine regulators might contribute to fitness and adaptability and, thus, to resistance to potential disease-causing insults. A better understanding of the posttranslational regulation of the microtubule cytoskeleton may substantially change the way we perceive the roles for the cytoskeleton in human disease. As enzymes catalyzing posttranslational modifications are accessible targets for drug development (Huq and Wei, 2010Huq M.D.M. Wei L.-N. Protein Posttranslational Modification: A Potential Target in Pharmaceutical Development.Pharmaceutical Sciences Encyclopedia. John Wiley & Sons, Inc., Hoboken, NJ, USA2010: 1-26Crossref Google Scholar), small-molecule inhibitors of tubulin-modifying enzymes are promising candidates for drugs for an emerging panoply of pathologies related to aberrant tubulin modifications.