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The tubulin code and its role in controlling microtubule properties and functions

Abstract

Microtubules are core components of the eukaryotic cytoskeleton with essential roles in cell division, shaping, motility and intracellular transport. Despite their functional heterogeneity, microtubules have a highly conserved structure made from almost identical molecular building blocks: the tubulin proteins. Alternative tubulin isotypes and a variety of post-translational modifications control the properties and functions of the microtubule cytoskeleton, a concept known as the ‘tubulin code’. Here we review the current understanding of the molecular components of the tubulin code and how they impact microtubule properties and functions. We discuss how tubulin isotypes and post-translational modifications control microtubule behaviour at the molecular level and how this translates into physiological functions at the cellular and organism levels. We then go on to show how fine-tuning of microtubule function by some tubulin modifications can affect homeostasis and how perturbation of this fine-tuning can lead to a range of dysfunctions, many of which are linked to human disease.

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Fig. 1: The elements of the tubulin code.
Fig. 2: The tubulin code impacts microtubule properties.
Fig. 3: The tubulin code impacts MAP–microtubule interactions.
Fig. 4: Cellular and physiological roles of the tubulin code.

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References

  1. Gittes, F., Mickey, B., Nettleton, J. & Howard, J. Flexural rigidity of microtubules and actin filaments measured from thermal fluctuations in shape. J. Cell Biol. 120, 923–934 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Vicente, J. J. & Wordeman, L. The quantification and regulation of microtubule dynamics in the mitotic spindle. Curr. Opin. Cell Biol. 60, 36–43 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Redemann, S., Furthauer, S., Shelley, M. & Muller-Reichert, T. Current approaches for the analysis of spindle organization. Curr. Opin. Struct. Biol. 58, 269–277 (2019).

    Article  CAS  PubMed  Google Scholar 

  4. Prosser, S. L. & Pelletier, L. Mitotic spindle assembly in animal cells: a fine balancing act. Nat. Rev. Mol. Cell Biol. 18, 187–201 (2017).

    Article  CAS  PubMed  Google Scholar 

  5. Ishikawa, T. Structural biology of cytoplasmic and axonemal dyneins. J. Struct. Biol. 179, 229–234 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Ichikawa, M. & Bui, K. H. Microtubule inner proteins: a meshwork of luminal proteins stabilizing the doublet microtubule. Bioessays 40, 1700209 (2018).

    Article  CAS  Google Scholar 

  7. Nachury, M. V. & Mick, D. U. Establishing and regulating the composition of cilia for signal transduction. Nat. Rev. Mol. Cell Biol. 20, 389–405 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. van Beuningen, S. F. & Hoogenraad, C. C. Neuronal polarity: remodeling microtubule organization. Curr. Opin. Neurobiol. 39, 1–7 (2016).

    Article  PubMed  CAS  Google Scholar 

  9. Guedes-Dias, P. & Holzbaur, E. L. F. Axonal transport: driving synaptic function. Science 366, aaw9997 (2019).

    Article  CAS  Google Scholar 

  10. Kelliher, M. T., Saunders, H. A. & Wildonger, J. Microtubule control of functional architecture in neurons. Curr. Opin. Neurobiol. 57, 39–45 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mitchison, T. & Kirschner, M. Dynamic instability of microtubule growth. Nature 312, 237–242 (1984). Mitchison and Kirscher demonstrate for the first time that microtubules undergo dynamic instability: they constantly switch between phases of polymerization and depolymerization.

    Article  CAS  PubMed  Google Scholar 

  12. Borisy, G. et al. Microtubules: 50 years on from the discovery of tubulin. Nat. Rev. Mol. Cell Biol. 17, 322–328 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gall, J. G. Microtubule fine structure. J. Cell Biol. 31, 639–643 (1966).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Witman, G. B., Carlson, K., Berliner, J. & Rosenbaum, J. L. Chlamydomonas flagella. I. Isolation and electrophoretic analysis of microtubules, matrix, membranes, and mastigonemes. J. Cell Biol. 54, 507–539 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nogales, E., Wolf, S. G. & Downing, K. H. Structure of the alpha beta tubulin dimer by electron crystallography. Nat. 391, 199–203 (1998).

    Article  CAS  Google Scholar 

  16. Alushin, G. M. et al. High-resolution microtubule structures reveal the structural transitions in alphabeta-tubulin upon GTP hydrolysis. Cell 157, 1117–1129 (2014). This study provides the first high-resolution structure of an entire microtubule, using cryo-electron microscopy, revealing differences between the GDP form and the GTP form of tubulin and the mechanism of dynamic instability of microtubules.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang, R., Alushin, G. M., Brown, A. & Nogales, E. Mechanistic origin of microtubule dynamic instability and its modulation by EB proteins. Cell 162, 849–859 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gigant, B. et al. The 4 Å X-ray structure of a tubulin:stathmin-like domain complex. Cell 102, 809–816 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Manka, S. W. & Moores, C. A. The role of tubulin-tubulin lattice contacts in the mechanism of microtubule dynamic instability. Nat. Struct. Mol. Biol. 25, 607–615 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Akhmanova, A. & Steinmetz, M. O. Control of microtubule organization and dynamics: two ends in the limelight. Nat. Rev. Mol. Cell Biol. 16, 711–726 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. Bodakuntla, S., Jijumon, A. S., Villablanca, C., Gonzalez-Billault, C. & Janke, C. Microtubule-associated proteins: structuring the cytoskeleton. Trends Cell Biol. 29, 804–819 (2019).

    Article  CAS  PubMed  Google Scholar 

  22. Karsenti, E., Nedelec, F. & Surrey, T. Modelling microtubule patterns. Nat. Cell Biol. 8, 1204–1211 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Nedelec, F., Surrey, T. & Karsenti, E. Self-organisation and forces in the microtubule cytoskeleton. Curr. Opin. Cell Biol. 15, 118–124 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Ishikawa, T. Axoneme structure from motile cilia. Cold Spring Harb. Perspect. Biol. 9, a028076 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Lin, J. & Nicastro, D. Asymmetric distribution and spatial switching of dynein activity generates ciliary motility. Science 360, eaar1968 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Verhey, K. J. & Gaertig, J. The tubulin code. Cell Cycle 6, 2152–2160 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Fulton, C. & Simpson, P. A. in Cell Motility (eds. Goldman, R., Pollard, T. & Rosenbaum, J. L.) 987–1005 (Cold Spring Harbor, 1976).

  28. Luduena, R. F. Multiple forms of tubulin: different gene products and covalent modifications. Int. Rev. Cytol. 178, 207–275 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Howes, S. C. et al. Structural differences between yeast and mammalian microtubules revealed by cryo-EM. J. Cell Biol. 216, 2669–2677 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chaaban, S. et al. The structure and dynamics of C. elegans tubulin reveals the mechanistic basis of microtubule growth. Dev. Cell 47, 191–204 (2018). This is the first study to directly determine the dynamic properties of C. elegans tubulin and to highlight differences from mammalian tubulin.

    Article  CAS  PubMed  Google Scholar 

  31. Schatz, P. J., Pillus, L., Grisafi, P., Solomon, F. & Botstein, D. Two functional alpha-tubulin genes of the yeast Saccharomyces cerevisiae encode divergent proteins. Mol. Cell Biol. 6, 3711–3721 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Neff, N. F., Thomas, J. H., Grisafi, P. & Botstein, D. Isolation of the beta-tubulin gene from yeast and demonstration of its essential function in vivo. Cell 33, 211–219 (1983).

    Article  CAS  PubMed  Google Scholar 

  33. HUGO Gene Nomenclature Committee. Gene Group: Tubulins. genenames.org https://www.genenames.org/data/genegroup/#!/group/778 (2020).

  34. Khodiyar, V. K. et al. A revised nomenclature for the human and rodent alpha-tubulin gene family. Genomics 90, 285–289 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Wang, D., Villasante, A., Lewis, S. A. & Cowan, N. J. The mammalian beta-tubulin repertoire: hematopoietic expression of a novel, heterologous beta-tubulin isotype. J. Cell Biol. 103, 1903–1910 (1986).

    Article  CAS  PubMed  Google Scholar 

  36. Schwer, H. D. et al. A lineage-restricted and divergent beta-tubulin isoform is essential for the biogenesis, structure and function of blood platelets. Curr. Biol. 11, 579–586 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Kimble, M., Incardona, J. P. & Raff, E. C. A variant beta-tubulin isoform of Drosophila melanogaster (beta 3) is expressed primarily in tissues of mesodermal origin in embryos and pupae, and is utilized in populations of transient microtubules. Dev. Biol. 131, 415–429 (1989).

    Article  CAS  PubMed  Google Scholar 

  38. Hoyle, H. D. & Raff, E. C. Two Drosophila beta tubulin isoforms are not functionally equivalent. J. Cell Biol. 111, 1009–1026 (1990). This study is the first to directly demonstrate functional singularity of tubulin isotypes.

    Article  CAS  PubMed  Google Scholar 

  39. Eipper, B. A. Properties of rat brain tubulin. J. Biol. Chem. 249, 1407–1416 (1974).

    CAS  PubMed  Google Scholar 

  40. Gard, D. L. & Kirschner, M. W. A polymer-dependent increase in phosphorylation of beta-tubulin accompanies differentiation of a mouse neuroblastoma cell line. J. Cell Biol. 100, 764–774 (1985).

    Article  CAS  PubMed  Google Scholar 

  41. Burke, B. E. & DeLorenzo, R. J. Ca2+ and calmodulin-dependent phosphorylation of endogenous synaptic vesicle tubulin by a vesicle-bound calmodulin kinase system. J. Neurochem. 38, 1205–1218 (1982).

    Article  CAS  PubMed  Google Scholar 

  42. Akiyama, T. et al. Substrate specificities of tyrosine-specific protein kinases toward cytoskeletal proteins in vitro. J. Biol. Chem. 261, 14797–14803 (1986).

    CAS  PubMed  Google Scholar 

  43. Hargreaves, A. J., Wandosell, F. & Avila, J. Phosphorylation of tubulin enhances its interaction with membranes. Nature 323, 827–828 (1986).

    Article  CAS  PubMed  Google Scholar 

  44. Wandosell, F., Serrano, L., Hernandez, M. A. & Avila, J. Phosphorylation of tubulin by a calmodulin-dependent protein kinase. J. Biol. Chem. 261, 10332–10339 (1986).

    CAS  PubMed  Google Scholar 

  45. Serrano, L., Diaz-Nido, J., Wandosell, F. & Avila, J. Tubulin phosphorylation by casein kinase II is similar to that found in vivo. J. Cell Biol. 105, 1731–1739 (1987).

    Article  CAS  PubMed  Google Scholar 

  46. Wandosell, F., Serrano, L. & Avila, J. Phosphorylation of alpha-tubulin carboxyl-terminal tyrosine prevents its incorporation into microtubules. J. Biol. Chem. 262, 8268–8273 (1987).

    CAS  PubMed  Google Scholar 

  47. Ludueña, R. F., Zimmermann, H. P. & Little, M. Identification of the phosphorylated beta-tubulin isotype in differentiated neuroblastoma cells. FEBS Lett. 230, 142–146 (1988).

    Article  PubMed  Google Scholar 

  48. Diaz-Nido, J., Serrano, L., Lopez-Otin, C., Vandekerckhove, J. & Avila, J. Phosphorylation of a neuronal-specific beta-tubulin isotype. J. Biol. Chem. 265, 13949–13954 (1990).

    CAS  PubMed  Google Scholar 

  49. Matten, W. T., Aubry, M., West, J. & Maness, P. F. Tubulin is phosphorylated at tyrosine by pp60c-src in nerve growth cone membranes. J. Cell Biol. 111, 1959–1970 (1990).

    Article  CAS  PubMed  Google Scholar 

  50. Zhou, R. P. et al. Ability of the c-mos product to associate with and phosphorylate tubulin. Science 251, 671–675 (1991).

    Article  CAS  PubMed  Google Scholar 

  51. Peters, J. D., Furlong, M. T., Asai, D. J., Harrison, M. L. & Geahlen, R. L. Syk, activated by cross-linking the B-cell antigen receptor, localizes to the cytosol where it interacts with and phosphorylates alpha-tubulin on tyrosine. J. Biol. Chem. 271, 4755–4762 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Zyss, D. et al. The Syk tyrosine kinase localizes to the centrosomes and negatively affects mitotic progression. Cancer Res. 65, 10872–10880 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Fourest-Lieuvin, A. et al. Microtubule regulation in mitosis: tubulin phosphorylation by the cyclin-dependent kinase Cdk1. Mol. Biol. Cell 17, 1041–1050 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sulimenko, V. et al. Regulation of microtubule formation in activated mast cells by complexes of gamma-tubulin with Fyn and Syk kinases. J. Immunol. 176, 7243–7253 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Ori-McKenney, K. M. et al. Phosphorylation of β-tubulin by the Down syndrome kinase, Minibrain/DYRK1a, regulates microtubule dynamics and dendrite morphogenesis. Neuron 90, 551–563 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. L’Hernault, S. W. & Rosenbaum, J. L. Chlamydomonas alpha-tubulin is posttranslationally modified by acetylation on the epsilon-amino group of a lysine. Biochemistry 24, 473–478 (1985).

    Article  PubMed  Google Scholar 

  57. Park, I. Y. et al. Dual chromatin and cytoskeletal remodeling by SETD2. Cell 166, 950–962 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ozols, J. & Caron, J. M. Posttranslational modification of tubulin by palmitoylation: II. Identification of sites of palmitoylation. Mol. Biol. Cell 8, 637–645 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ren, Y., Zhao, J. & Feng, J. Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. J. Neurosci. 23, 3316–3324 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, Q., Peng, Z., Long, H., Deng, X. & Huang, K. Polyubiquitylation of alpha-tubulin at K304 is required for flagellar disassembly in Chlamydomonas. J. Cell Sci. 132, jcs229047 (2019).

    Article  CAS  PubMed  Google Scholar 

  61. Song, Y. et al. Transglutaminase and polyamination of tubulin: posttranslational modification for stabilizing axonal microtubules. Neuron 78, 109–123 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Barra, H. S., Arcce, C. A., Rodriguez, J. A. & Caputto, R. Incorporation of phenylalanine as a single unit into rat brain protein: reciprocal inhibition by phenylalanine and tyrosine of their respective incorporations. J. Neurochem. 21, 1241–1251 (1973).

    Article  CAS  PubMed  Google Scholar 

  63. Arce, C. A., Rodriguez, J. A., Barra, H. S. & Caputto, R. Incorporation of L-tyrosine, L-phenylalanine and L-3,4-dihydroxyphenylalanine as single units into rat brain tubulin. Eur. J. Biochem. 59, 145–149 (1975).

    Article  CAS  PubMed  Google Scholar 

  64. Eddé, B. et al. Posttranslational glutamylation of alpha-tubulin. Science 247, 83–85 (1990).

    Article  PubMed  Google Scholar 

  65. Alexander, J. E. et al. Characterization of posttranslational modifications in neuron-specific class III beta-tubulin by mass spectrometry. Proc. Natl Acad. Sci. USA 88, 4685–4689 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rüdiger, M., Plessman, U., Kloppel, K. D., Wehland, J. & Weber, K. Class II tubulin, the major brain beta tubulin isotype is polyglutamylated on glutamic acid residue 435. FEBS Lett. 308, 101–105 (1992).

    Article  PubMed  Google Scholar 

  67. Redeker, V. et al. Polyglycylation of tubulin: a posttranslational modification in axonemal microtubules. Science 266, 1688–1691 (1994).

    Article  CAS  PubMed  Google Scholar 

  68. Rodriguez, J. A., Arce, C. A., Barra, H. S. & Caputto, R. Release of tyrosine incorporated as a single unit into rat brain protein. Biochem. Biophys. Res. Commun. 54, 335–340 (1973). This is the first description of detyrosination. In this study, it was not yet known that the detyrosinated protein is tubulin.

    Article  CAS  PubMed  Google Scholar 

  69. Hallak, M. E., Rodriguez, J. A., Barra, H. S. & Caputto, R. Release of tyrosine from tyrosinated tubulin. Some common factors that affect this process and the assembly of tubulin. FEBS Lett. 73, 147–150 (1977).

    Article  CAS  PubMed  Google Scholar 

  70. Paturle, L., Wehland, J., Margolis, R. L. & Job, D. Complete separation of tyrosinated, detyrosinated, and nontyrosinatable brain tubulin subpopulations using affinity chromatography. Biochemistry 28, 2698–2704 (1989).

    Article  CAS  PubMed  Google Scholar 

  71. Paturle-Lafanechere, L. et al. Characterization of a major brain tubulin variant which cannot be tyrosinated. Biochemistry 30, 10523–10528 (1991).

    Article  CAS  PubMed  Google Scholar 

  72. Aillaud, C. et al. Evidence for new C-terminally truncated variants of alpha- and beta-tubulins. Mol. Biol. Cell 27, 640–653 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kumar, N. & Flavin, M. Preferential action of a brain detyrosinolating carboxypeptidase on polymerized tubulin. J. Biol. Chem. 256, 7678–7686 (1981).

    CAS  PubMed  Google Scholar 

  74. Shida, T., Cueva, J. G., Xu, Z., Goodman, M. B. & Nachury, M. V. The major alpha-tubulin K40 acetyltransferase alphaTAT1 promotes rapid ciliogenesis and efficient mechanosensation. Proc. Natl Acad. Sci. USA 107, 21517–21522 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Regnard, C., Audebert, S., Desbruyeres, Denoulet, P. & Eddé, B. Tubulin polyglutamylase: partial purification and enzymatic properties. Biochemistry 37, 8395–8404 (1998).

    Article  CAS  PubMed  Google Scholar 

  76. Audebert, S. et al. Reversible polyglutamylation of alpha- and beta-tubulin and microtubule dynamics in mouse brain neurons. Mol. Biol. Cell 4, 615–626 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Szyk, A., Deaconescu, A. M., Piszczek, G. & Roll-Mecak, A. Tubulin tyrosine ligase structure reveals adaptation of an ancient fold to bind and modify tubulin. Nat. Struct. Mol. Biol. 18, 1250–1258 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Prota, A. E. et al. Structural basis of tubulin tyrosination by tubulin tyrosine ligase. J. Cell Biol. 200, 259–270 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Szyk, A., Piszczek, G. & Roll-Mecak, A. Tubulin tyrosine ligase and stathmin compete for tubulin binding invitro. J. Mol. Biol. 425, 2412–2414 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Cheng, Y., Glaeser, R. M. & Nogales, E. How cryo-EM became so hot. Cell 171, 1229–1231 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kellogg, E. H. et al. Near-atomic model of microtubule-tau interactions. Science 360, 1242–1246 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Howes, S. C. et al. Structural and functional differences between porcine brain and budding yeast microtubules. Cell Cycle 17, 278–287 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Minoura, I. et al. Overexpression, purification, and functional analysis of recombinant human tubulin dimer. FEBS Lett. 587, 3450–3455 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Vemu, A. et al. Structure and dynamics of single-isoform recombinant neuronal human tubulin. J. Biol. Chem. 291, 12907–12915 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ti, S.-C., Alushin, G. M. & Kapoor, T. M. Human β-tubulin isotypes can regulate microtubule protofilament number and stability. Dev. Cell 47, 175–190 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chalfie, M. & Thomson, J. N. Structural and functional diversity in the neuronal microtubules of Caenorhabditis elegans. J. Cell Biol. 93, 15–23 (1982).

    Article  CAS  PubMed  Google Scholar 

  87. Fukushige, T. et al. MEC-12, an alpha-tubulin required for touch sensitivity in C. elegans. J. Cell Sci. 112, 395–403 (1999).

    CAS  PubMed  Google Scholar 

  88. Savage, C. et al. mec-7 is a β-tubulin gene required for the production of 15-protofilament microtubules in Caenorhabditis elegans. Genes Dev. 3, 870–881 (1989).

    Article  CAS  PubMed  Google Scholar 

  89. Hurd, D. D., Miller, R. M., Nunez, L. & Portman, D. S. Specific alpha- and beta-tubulin isotypes optimize the functions of sensory cilia in Caenorhabditis elegans. Genetics 185, 883–896 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Silva, M. et al. Cell-specific alpha-tubulin isotype regulates ciliary microtubule ultrastructure, intraflagellar transport, and extracellular vesicle biology. Curr. Biol. 27, 968–980 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Raff, E. C., Fackenthal, J. D., Hutchens, J. A.,Hoyle, H. D. & Turner, F. R. Microtubule architecture specified by a beta-tubulin isoform. Science 275, 70–73 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Bechstedt, S. & Brouhard, Gary J. Doublecortin recognizes the 13-protofilament microtubule cooperatively and tracks microtubule ends. Dev. Cell 23, 181–192 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Topalidou, I. et al. Genetically separable functions of the MEC-17 tubulin acetyltransferase affect microtubule organization. Curr. Biol. 22, 1057–1065 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Cueva, J. G., Hsin, J., Huang, K. C. & Goodman, M. B. Posttranslational acetylation of alpha-tubulin constrains protofilament number in native microtubules. Curr. Biol. 22, 1066–1074 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Konno, A. et al. Ttll9-/- mice sperm flagella show shortening of doublet 7, reduction of doublet 5 polyglutamylation and a stall in beating. J. Cell Sci. 129, 2757–2766 (2016).

    Article  CAS  PubMed  Google Scholar 

  96. Wang, C., Guo, Z., Wang, R. & Luo, Y. Role of the inter-protofilament sliding in the bending of protein microtubules. J. Biomech. 49, 3803–3807 (2016).

    Article  PubMed  Google Scholar 

  97. Chretien, D., Flyvbjerg, H. & Fuller, S. D. Limited flexibility of the inter-protofilament bonds in microtubules assembled from pure tubulin. Eur. Biophys. J. 27, 490–500 (1998).

    Article  CAS  PubMed  Google Scholar 

  98. Machlus, K. R. & Italiano, J. E. Jr. The incredible journey: from megakaryocyte development to platelet formation. J. Cell Biol. 201, 785–796 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kunishima, S., Kobayashi, R., Itoh, T. J., Hamaguchi, M. & Saito, H. Mutation of the beta1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly. Blood 113, 458–461 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Thon, J. N. et al. Microtubule and cortical forces determine platelet size during vascular platelet production. Nat. Commun. 3, 852 (2012).

    Article  PubMed  CAS  Google Scholar 

  101. Dmitrieff, S., Alsina, A., Mathur, A. & Nedelec, F. J. Balance of microtubule stiffness and cortical tension determines the size of blood cells with marginal band across species. Proc. Natl Acad. Sci. USA 114, 4418–4423 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. LeDizet, M. & Piperno, G. Identification of an acetylation site of Chlamydomonas alpha-tubulin. Proc. Natl Acad. Sci. USA 84, 5720–5724 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Janke, C. & Montagnac, G. Causes and consequences of microtubule acetylation. Curr. Biol. 27, R1287–R1292 (2017).

    Article  CAS  PubMed  Google Scholar 

  104. Portran, D., Schaedel, L., Xu, Z., Thery, M. & Nachury, M. V. Tubulin acetylation protects long-lived microtubules against mechanical ageing. Nat. Cell Biol. 19, 391–398 (2017). This study demonstrates how tubulin acetylation changes the mechanical properties of microtubules, protecting them from damage after repetitive bending.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Xu, Z. et al. Microtubules acquire resistance from mechanical breakage through intralumenal acetylation. Science 356, 328–332 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Eshun-Wilson, L. et al. Effects of alpha-tubulin acetylation on microtubule structure and stability. Proc. Natl Acad. Sci. USA 116, 10366–10371 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Strassel, C. et al. An essential role for α4A-tubulin in platelet biogenesis. Life Sci. Alliance 2, e201900309 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Kerr, J. P. et al. Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle. Nat. Commun. 6, 8526 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Robison, P. et al. Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes. Science 352, aaf0659 (2016). This study shows for the first time how microtubules buckle at high frequency in contracting heart muscle cells and how this behaviour is dependent on tubulin detyrosination.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Banerjee, A. et al. A monoclonal antibody against the type II isotype of beta-tubulin. Preparation of isotypically altered tubulin. J. Biol. Chem. 263, 3029–3034 (1988).

    CAS  PubMed  Google Scholar 

  111. Banerjee, A., Roach, M. C., Trcka, P. & Ludueña, R. F. Increased microtubule assembly in bovine brain tubulin lacking the type III isotype of beta-tubulin. J. Biol. Chem. 265, 1794–1799 (1990).

    CAS  PubMed  Google Scholar 

  112. Banerjee, A., Roach, M. C., Trcka, P. & Ludueña, R. F. Preparation of a monoclonal antibody specific for the class IV isotype of beta-tubulin. Purification and assembly of alpha beta II, alpha beta III, and alpha beta IV tubulin dimers from bovine brain. J. Biol. Chem. 267, 5625–5630 (1992).

    CAS  PubMed  Google Scholar 

  113. Lu, Q. & Luduena, R. F. In vitro analysis of microtubule assembly of isotypically pure tubulin dimers. Intrinsic differences in the assembly properties of alpha beta II, alpha beta III, and alpha beta IV tubulin dimers in the absence of microtubule-associated proteins. J. Biol. Chem. 269, 2041–2047 (1994).

    CAS  PubMed  Google Scholar 

  114. Panda, D., Miller, H. P., Banerjee, A., Ludueña, R. F. & Wilson, L. Microtubule dynamics in vitro are regulated by the tubulin isotype composition. Proc. Natl Acad. Sci. USA 91, 11358–11362 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pamula, M. C., Ti, S.-C. & Kapoor, T. M. The structured core of human beta tubulin confers isotype-specific polymerization properties. J. Cell Biol. 213, 425–433 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Denoulet, P., Eddé, B. & Gros, F. Differential expression of several neurospecific beta-tubulin mRNAs in the mouse brain during development. Gene 50, 289–297 (1986).

    Article  CAS  PubMed  Google Scholar 

  117. Chu, C.-W. et al. A novel acetylation of beta-tubulin by San modulates microtubule polymerization via down-regulating tubulin incorporation. Mol. Biol. Cell 22, 448–456 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wang, Q., Crevenna, A. H., Kunze, I. & Mizuno, N. Structural basis for the extended CAP-Gly domains of p150glued binding to microtubules and the implication for tubulin dynamics. Proc. Natl Acad. Sci. USA 111, 11347–11352 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Manna, T., Honnappa, S., Steinmetz, M. O. & Wilson, L. Suppression of microtubule dynamic instability by the +TIP protein EB1 and its modulation by the CAP-Gly domain of p150glued. Biochemistry 47, 779–786 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Lopus, M. et al. Cooperative stabilization of microtubule dynamics by EB1 and CLIP-170 involves displacement of stably bound Pi at microtubule ends. Biochemistry 51, 3021–3030 (2012).

    Article  CAS  PubMed  Google Scholar 

  121. Peris, L. et al. Motor-dependent microtubule disassembly driven by tubulin tyrosination. J. Cell Biol. 185, 1159–1166 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lacroix, B. et al. Tubulin polyglutamylation stimulates spastin-mediated microtubule severing. J. Cell Biol. 189, 945–954 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Valenstein, M. L. & Roll-Mecak, A. Graded control of microtubule severing by tubulin glutamylation. Cell 164, 911–921 (2016). Valenstein and Roll-Mecak show for the first time that different degrees of polyglutamylation differentially regulate spastin-mediated microtubule severing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Shin, S. C. et al. Structural and molecular basis for katanin-mediated severing of glutamylated microtubules. Cell Rep. 26, 1357–1367 (2019).

    Article  CAS  PubMed  Google Scholar 

  125. Kuo, Y.-W., Trottier, O., Mahamdeh, M. & Howard, J. Spastin is a dual-function enzyme that severs microtubules and promotes their regrowth to increase the number and mass of microtubules. Proc. Natl Acad. Sci. USA 116, 5533–5541 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Boucher, D., Larcher, J. C., Gros, F. & Denoulet, P. Polyglutamylation of tubulin as a progressive regulator of in vitro interactions between the microtubule-associated protein tau and tubulin. Biochemistry 33, 12471–12477 (1994).

    Article  CAS  PubMed  Google Scholar 

  127. Bonnet, C. et al. Differential binding regulation of microtubule-associated proteins MAP1A, MAP1B, and MAP2 by tubulin polyglutamylation. J. Biol. Chem. 276, 12839–12848 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Lane, T. R., Fuchs, E. & Slep, K. C. Structure of the ACF7 EF-HAND-GAR module and delineation of microtubule binding determinants. Structure 25, 1130–1138 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhang, R., Roostalu, J., Surrey, T. & Nogales, E. Structural insight into TPX2-stimulated microtubule assembly. eLife 6, e30959 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Nithianantham, S. et al. Structural basis of tubulin recruitment and assembly by microtubule polymerases with tumor overexpressed gene (TOG) domain arrays. eLife 7, e38922 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Shigematsu, H. et al. Structural insight into microtubule stabilization and kinesin inhibition by tau family MAPs. J. Cell Biol. 217, 4155–4163 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Alushin, G. M. et al. Multimodal microtubule binding by the Ndc80 kinetochore complex. Nat. Struct. Mol. Biol. 19, 1161–1167 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Atherton, J. et al. A structural model for microtubule minus-end recognition and protection by CAMSAP proteins. Nat. Struct. Mol. Biol. 24, 931–943 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Adib, R. et al. Mitotic phosphorylation by NEK6 and NEK7 reduces the microtubule affinity of EML4 to promote chromosome congression. Sci. Signal. 12, eaaw2939 (2019).

    Article  PubMed  CAS  Google Scholar 

  135. Cambray-Deakin, M. A. & Burgoyne, R. D. The non-tyrosinated M alpha 4 alpha-tubulin gene product is post-translationally tyrosinated in adult rat cerebellum. Brain Res. Mol. Brain Res 8, 77–81 (1990).

    Article  CAS  PubMed  Google Scholar 

  136. Gu, W., Lewis, S. A. & Cowan, N. J. Generation of antisera that discriminate among mammalian alpha-tubulins: introduction of specialized isotypes into cultured cells results in their coassembly without disruption of normal microtubule function. J. Cell Biol. 106, 2011–2022 (1988).

    Article  CAS  PubMed  Google Scholar 

  137. Natarajan, K., Gadadhar, S., Souphron, J., Magiera, M. M. & Janke, C. Molecular interactions between tubulin tails and glutamylases reveal determinants of glutamylation patterns. EMBO Rep. 18, 1013–1026 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kumar, N. & Flavin, M. Modulation of some parameters of assembly of microtubules in vitro by tyrosinolation of tubulin. Eur. J. Biochem. 128, 215–222 (1982).

    Article  CAS  PubMed  Google Scholar 

  139. Peris, L. et al. Tubulin tyrosination is a major factor affecting the recruitment of CAP-Gly proteins at microtubule plus ends. J. Cell Biol. 174, 839–849 (2006). This study identifies tubulin tyrosination as an essential factor for the microtubule plus end localization of CAP-Gly proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Bieling, P. et al. CLIP-170 tracks growing microtubule ends by dynamically recognizing composite EB1/tubulin-binding sites. J. Cell Biol. 183, 1223–1233 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Weisbrich, A. et al. Structure-function relationship of CAP-Gly domains. Nat. Struct. Mol. Biol. 14, 959–967 (2007).

    Article  CAS  PubMed  Google Scholar 

  142. Cambray-Deakin, M. A. & Burgoyne, R. D. Acetylated and detyrosinated alpha-tubulins are co-localized in stable microtubules in rat meningeal fibroblasts. Cell Motil. Cytoskeleton 8, 284–291 (1987).

    Article  CAS  PubMed  Google Scholar 

  143. Kreis, T. E. Microtubules containing detyrosinated tubulin are less dynamic. EMBO J. 6, 2597–2606 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Webster, D. R., Gundersen, G. G., Bulinski, J. C. & Borisy, G. G. Differential turnover of tyrosinated and detyrosinated microtubules. Proc. Natl Acad. Sci. USA 84, 9040–9044 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sirajuddin, M., Rice, L. M. & Vale, R. D. Regulation of microtubule motors by tubulin isotypes and post-translational modifications. Nat. Cell Biol. 16, 335–344 (2014). This is the first study to directly measure the impact of a range of tubulin PTMs on several motor proteins using recombinant, chimeric yeast tubulin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Barisic, M. et al. Microtubule detyrosination guides chromosomes during mitosis. Science 348, 799–803 (2015). This study is the first to directly reveal a function of a tubulin PTM during cell division.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Souphron, J. et al. Purification of tubulin with controlled post-translational modifications by polymerization–depolymerization cycles. Nat. Protoc. 14, 1634–1660 (2019).

    Article  CAS  PubMed  Google Scholar 

  148. McKenney, R. J., Huynh, W., Vale, R. D. & Sirajuddin, M. Tyrosination of alpha-tubulin controls the initiation of processive dynein-dynactin motility. EMBO J. 35, 1175–1185 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. McNally, F. J. & Roll-Mecak, A. Microtubule-severing enzymes: From cellular functions to molecular mechanism. J. Cell Biol. 217, 4057–4069 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Larcher, J. C., Boucher, D., Lazereg, S., Gros, F. & Denoulet, P. Interaction of kinesin motor domains with alpha- and beta-tubulin subunits at a tau-independent binding site. Regulation by polyglutamylation. J. Biol. Chem. 271, 22117–22124 (1996).

    Article  CAS  PubMed  Google Scholar 

  151. Bonnet, C. et al. Interaction of STOP with neuronal tubulin is independent of polyglutamylation. Biochem. Biophys. Res. Commun. 297, 787–793 (2002).

    Article  CAS  PubMed  Google Scholar 

  152. van Dijk, J. et al. A targeted multienzyme mechanism for selective microtubule polyglutamylation. Mol. Cell 26, 437–448 (2007).

    Article  PubMed  CAS  Google Scholar 

  153. Konishi, Y. & Setou, M. Tubulin tyrosination navigates the kinesin-1 motor domain to axons. Nat. Neurosci. 12, 559–567 (2009).

    Article  CAS  PubMed  Google Scholar 

  154. Dunn, S. et al. Differential trafficking of Kif5c on tyrosinated and detyrosinated microtubules in live cells. J. Cell Sci. 121, 1085–1095 (2008).

    Article  CAS  PubMed  Google Scholar 

  155. Mohan, N., Sorokina, E. M., Verdeny, I. V., Alvarez, A. S. & Lakadamyali, M. Detyrosinated microtubules spatially constrain lysosomes facilitating lysosome-autophagosome fusion. J. Cell Biol. 218, 632–643 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Reed, N. A. et al. Microtubule acetylation promotes kinesin-1 binding and transport. Curr. Biol. 16, 2166–2172 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. Godena, V. K. et al. Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat. Commun. 5, 5245 (2014).

    Article  CAS  PubMed  Google Scholar 

  158. Kim, J.-Y. 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 Cell Int. 2016, 9475981 (2016).

    Google Scholar 

  159. Guo, W. et al. HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients. Nat. Commun. 8, 861 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Morelli, G. et al. p27Kip1 modulates axonal transport by regulating alpha-tubulin acetyltransferase 1 stability. Cell Rep. 23, 2429–2442 (2018).

    Article  CAS  PubMed  Google Scholar 

  161. Dompierre, J. P. et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J. Neurosci. 27, 3571–3583 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Zhang, Y. et al. Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol. Cell Biol. 28, 1688–1701 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Kim, G.-W., Li, L., Gorbani, M., You, L. & Yang, X.-J. Mice lacking alpha-tubulin acetyltransferase 1 are viable but display alpha-tubulin acetylation deficiency and dentate gyrus distortion. J. Biol. Chem. 288, 20334–20350 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kalebic, N. et al. alphaTAT1 is the major alpha-tubulin acetyltransferase in mice. Nat. Commun. 4, 1962 (2013).

    Article  PubMed  CAS  Google Scholar 

  165. Walter, W. J., Beranek, V., Fischermeier, E. & Diez, S. Tubulin acetylation alone does not affect kinesin-1 velocity and run length in vitro. PLoS One 7, e42218 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Kaul, N., Soppina, V. & Verhey, K. J. Effects of alpha-tubulin K40 acetylation and detyrosination on kinesin-1 motility in a purified system. Biophys. J. 106, 2636–2643 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Cai, D., McEwen, D. P., Martens, J. R., Meyhofer, E. & Verhey, K. J. Single molecule imaging reveals differences in microtubule track selection between kinesin motors. PLoS Biol. 7, e1000216 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Lessard, D. V. et al. Polyglutamylation of tubulin’s C-terminal tail controls pausing and motility of kinesin-3 family member KIF1A. J. Biol. Chem. 294, 6353–6363 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Barlan, K., Lu, W. & Gelfand, V. I. The microtubule-binding protein ensconsin is an essential cofactor of kinesin-1. Curr. Biol. 23, 317–322 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Semenova, I. et al. Regulation of microtubule-based transport by MAP4. Mol. Biol. Cell 25, 3119–3132 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Tymanskyj, S. R., Yang, B. H., Verhey, K. J. & Ma, L. MAP7 regulates axon morphogenesis by recruiting kinesin-1 to microtubules and modulating organelle transport. eLife 7, e36374 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Maas, C. et al. Synaptic activation modifies microtubules underlying transport of postsynaptic cargo. Proc. Natl Acad. Sci. USA 106, 8731–8736 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Even, A. et al. ATAT1-enriched vesicles promote microtubule acetylation via axonal transport. Sci. Adv. 5, eaax2705 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Monroy, B. Y. et al. Competition between microtubule-associated proteins directs motor transport. Nat. Commun. 9, 1487 (2018). This study describes how different MAPs can have differential effects on the behaviour of a given motor protein on microtubules.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Siahaan, V. et al. Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes. Nat. Cell Biol. 21, 1086–1092 (2019).

    Article  CAS  PubMed  Google Scholar 

  176. Tan, R. et al. Microtubules gate tau condensation to spatially regulate microtubule functions. Nat. Cell Biol. 21, 1078–1085 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Ramkumar, A., Jong, B. Y. & Ori-McKenney, K. M. ReMAPping the microtubule landscape: how phosphorylation dictates the activities of microtubule-associated proteins. Dev. Dyn. 247, 138–155 (2018).

    Article  CAS  PubMed  Google Scholar 

  178. Linck, R. W., Chemes, H. & Albertini, D. F. The axoneme: the propulsive engine of spermatozoa and cilia and associated ciliopathies leading to infertility. J. Assist. Reprod. Genet. 33, 141–156 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Ginger, M. L., Portman, N. & McKean, P. G. Swimming with protists: perception, motility and flagellum assembly. Nat. Rev. Microbiol. 6, 838–850 (2008).

    Article  CAS  PubMed  Google Scholar 

  180. Spassky, N. & Meunier, A. The development and functions of multiciliated epithelia. Nat. Rev. Mol. Cell Biol. 18, 423–436 (2017).

    Article  CAS  PubMed  Google Scholar 

  181. Kubo, T., Yanagisawa, H.-a, Yagi, T., Hirono, M. & Kamiya, R. Tubulin polyglutamylation regulates axonemal motility by modulating activities of inner-arm dyneins. Curr. Biol. 20, 441–445 (2010).

    Article  CAS  PubMed  Google Scholar 

  182. Suryavanshi, S. et al. Tubulin glutamylation regulates ciliary motility by altering inner dynein arm activity. Curr. Biol. 20, 435–440 (2010). Together with the work of Kubo et al. (2010), this is the first demonstration of a direct effect of tubulin polyglutamylation on axonemal dynein function and thus on ciliary beating.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Bosch Grau, M. et al. Tubulin glycylases and glutamylases have distinct functions in stabilization and motility of ependymal cilia. J. Cell Biol. 202, 441–451 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Lechtreck, K. F. & Geimer, S. Distribution of polyglutamylated tubulin in the flagellar apparatus of green flagellates. Cell Motil. Cytoskeleton 47, 219–235 (2000).

    Article  CAS  PubMed  Google Scholar 

  185. Orbach, R. & Howard, J. The dynamic and structural properties of axonemal tubulins support the high length stability of cilia. Nat. Commun. 10, 1838 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Wu, H.-Y., Wei, P. & Morgan, J. I. Role of cytosolic carboxypeptidase 5 in neuronal survival and spermatogenesis. Sci. Rep. 7, 41428 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Vogel, 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. 47, 703–712 (2010).

    Article  CAS  PubMed  Google Scholar 

  188. Mullen, R. J., Eicher, E. M. & Sidman, R. L. Purkinje cell degeneration, a new neurological mutation in the mouse. Proc. Natl Acad. Sci. USA 73, 208–212 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Giordano, T. et al. Loss of the deglutamylase CCP5 perturbs multiple steps of spermatogenesis and leads to male infertility. J. Cell Sci. 132, jcs226951 (2019).

    Article  CAS  PubMed  Google Scholar 

  190. Ikegami, 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 107, 10490–10495 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Wloga, D., Joachimiak, E., Louka, P. & Gaertig, J. Posttranslational modifications of tubulin and cilia. Cold Spring Harb. Perspect. Biol. 9, a028159 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Gadadhar, S. et al. Tubulin glycylation controls primary cilia length. J. Cell Biol. 216, 2701–2713 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Bosch Grau, M. et al. Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration. J. Cell Sci. 130, 938–949 (2017).

    Article  PubMed  CAS  Google Scholar 

  194. Wright, A. F., Chakarova, C. F., Abd El-Aziz, M. M. & Bhattacharya, S. S. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat. Rev. Genet. 11, 273–284 (2010).

    Article  CAS  PubMed  Google Scholar 

  195. Wloga, D. et al. Hyperglutamylation of tubulin can either stabilize or destabilize microtubules in the same cell. Eukaryot. Cell 9, 184–193 (2010).

    Article  CAS  PubMed  Google Scholar 

  196. Wloga, D. et al. TTLL3 Is a tubulin glycine ligase that regulates the assembly of cilia. Dev. Cell 16, 867–876 (2009).

    Article  CAS  PubMed  Google Scholar 

  197. Kastner, 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. 56, 8045–8053 (2015).

    Article  CAS  PubMed  Google Scholar 

  198. Astuti, G. D. N. et al. Mutations in AGBL5, encoding alpha-tubulin deglutamylase, are associated with autosomal recessive retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 57, 6180–6187 (2016).

    Article  CAS  PubMed  Google Scholar 

  199. Branham, K. et al. Establishing the involvement of the novel gene AGBL5 in retinitis pigmentosa by whole genome sequencing. Physiol. Genomics 48, 922–927 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Abu Diab, A. et al. The combination of whole-exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies. Acta Ophthalmol. 97, e877–e886 (2019).

    Article  CAS  PubMed  Google Scholar 

  201. Marchena, M. et al. The retina of the PCD/PCD mouse as a model of photoreceptor degeneration. A structural and functional study. Exp. Eye Res. 93, 607–617 (2011).

    Article  CAS  PubMed  Google Scholar 

  202. Sergouniotis, P. I. et al. Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy. Am. J. Hum. Genet. 94, 760–769 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Dias, M. d. S. et al. Novel splice-site mutation in TTLL5 causes cone dystrophy in a consanguineous family. Mol. Vis. 23, 131–139 (2017).

    PubMed  PubMed Central  Google Scholar 

  204. Sun, X. et al. Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations. Proc. Natl Acad. Sci. USA 113, E2925–2934 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Johnson, K. A. The axonemal microtubules of the Chlamydomonas flagellum differ in tubulin isoform content. J. Cell Sci. 111, 313–320 (1998).

    CAS  PubMed  Google Scholar 

  206. Reiter, J. F. & Leroux, M. R. Genes and molecular pathways underpinning ciliopathies. Nat. Rev. Mol. Cell Biol. 18, 533–547 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Hong, S.-R. et al. Spatiotemporal manipulation of ciliary glutamylation reveals its roles in intraciliary trafficking and Hedgehog signaling. Nat. Commun. 9, 1732 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Lee, J. E. et al. CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nat. Genet. 44, 193–199 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Bré, M. H. et al. Axonemal tubulin polyglycylation probed with two monoclonal antibodies: widespread evolutionary distribution, appearance during spermatozoan maturation and possible function in motility. J. Cell Sci. 109, 727–738 (1996).

    PubMed  Google Scholar 

  210. Adoutte, A., Claisse, M., Maunoury, R. & Beisson, J. Tubulin evolution: ciliate-specific epitopes are conserved in the ciliary tubulin of Metazoa. J. Mol. Evol. 22, 220–229 (1985).

    Article  CAS  PubMed  Google Scholar 

  211. Renthal, R., Schneider, B. G., Miller, M. M. & Ludueña, R. F. Beta IV is the major beta-tubulin isotype in bovine cilia. Cell Motil. Cytoskeleton 25, 19–29 (1993).

    Article  CAS  PubMed  Google Scholar 

  212. Raff, E. C., Hoyle, H. D., Popodi, E. M. & Turner, F. R. Axoneme beta-tubulin sequence determines attachment of outer dynein arms. Curr. Biol. 18, 911–914 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Schmidt-Cernohorska, M. et al. Flagellar microtubule doublet assembly in vitro reveals a regulatory role of tubulin C-terminal tails. Science 363, 285–288 (2019).

    Article  CAS  PubMed  Google Scholar 

  214. Eddé, B. et al. A combination of posttranslational modifications is responsible for the production of neuronal alpha-tubulin heterogeneity. J. Cell Biochem. 46, 134–142 (1991).

    Article  PubMed  Google Scholar 

  215. Mansfield, S. G. & Gordon-Weeks, P. R. Dynamic post-translational modification of tubulin in rat cerebral cortical neurons extending neurites in culture: effects of taxol. J. Neurocytol. 20, 654–666 (1991).

    Article  CAS  PubMed  Google Scholar 

  216. Cumming, R., Burgoyne, R. D. & Lytton, N. A. Immunocytochemical demonstration of alpha-tubulin modification during axonal maturation in the cerebellar cortex. J. Cell Biol. 98, 347–351 (1984).

    Article  CAS  PubMed  Google Scholar 

  217. Audebert, S. et al. Developmental regulation of polyglutamylated alpha- and beta-tubulin in mouse brain neurons. J. Cell Sci. 107, 2313–2322 (1994).

    CAS  PubMed  Google Scholar 

  218. Rodriguez, J. A. & Borisy, G. G. Modification of the C-terminus of brain tubulin during development. Biochem. Biophys. Res. Commun. 83, 579–586 (1978).

    Article  CAS  PubMed  Google Scholar 

  219. Raybin, D. & Flavin, M. Modification of tubulin by tyrosylation in cells and extracts and its effect on assembly in vitro. J. Cell Biol. 73, 492–504 (1977).

    Article  CAS  PubMed  Google Scholar 

  220. Carbajal, A., Chesta, M. E., Bisig, C. G. & Arce, C. A. A novel method for purification of polymerizable tubulin with a high content of the acetylated isotype. Biochem. J. 449, 643–648 (2013).

    Article  CAS  PubMed  Google Scholar 

  221. Ahmad, F. J., Pienkowski, T. P. & Baas, P. W. Regional differences in microtubule dynamics in the axon. J. Neurosci. 13, 856–866 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Brown, A., Li, Y., Slaughter, T. & Black, M. M. Composite microtubules of the axon: quantitative analysis of tyrosinated and acetylated tubulin along individual axonal microtubules. J. Cell Sci. 104, 339–352 (1993).

    CAS  PubMed  Google Scholar 

  223. Tas, R. P. et al. Differentiation between oppositely oriented microtubules controls polarized neuronal transport. Neuron 96, 1264–1271 (2017). Using super-resolution microscopy, the authors reveal the presence of different microtubule arrays within neuronal dendrites. These different arrays are characterized by specific tubulin PTMs and microtubule polarities, and are used by differently oriented transport complexes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Burton, P. R. & Paige, J. L. Polarity of axoplasmic microtubules in the olfactory nerve of the frog. Proc. Natl Acad. Sci. USA 78, 3269–3273 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Heidemann, S. R., Landers, J. M. & Hamborg, M. A. Polarity orientation of axonal microtubules. J. Cell Biol. 91, 661–665 (1981).

    Article  CAS  PubMed  Google Scholar 

  226. Erck, C. et al. A vital role of tubulin-tyrosine-ligase for neuronal organization. Proc. Natl Acad. Sci. USA 102, 7853–7858 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Marcos, S. et al. Tubulin tyrosination is required for the proper organization and pathfinding of the growth cone. PLoS One 4, e5405 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  228. Aillaud, C. et al. Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation. Science 358, 1448–1453 (2017).

    Article  CAS  PubMed  Google Scholar 

  229. Nieuwenhuis, J. et al. Vasohibins encode tubulin detyrosinating activity. Science 358, 1453–1456 (2017). This study co-discovers, together with Aillaud et al. (2017), the identity of tubulin detyrosinases as vasohibin-family proteins.

    Article  CAS  PubMed  Google Scholar 

  230. Iqbal, Z. et al. Loss of function of SVBP leads to autosomal recessive intellectual disability, microcephaly, ataxia, and hypotonia. Genet. Med. 21, 1790–1796 (2019).

    Article  CAS  PubMed  Google Scholar 

  231. Pagnamenta, A. T. et al. Defective tubulin detyrosination causes structural brain abnormalities with cognitive deficiency in humans and mice. Hum. Mol. Genet. 28, 3391–3405 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  232. Guimera, J. et al. A human homologue of Drosophila Minibrain (Mnb) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region. Hum. Mol. Genet. 5, 1305–1310 (1996).

    Article  CAS  PubMed  Google Scholar 

  233. Willsey, A. J. & State, M. W. Autism spectrum disorders: from genes to neurobiology. Curr. Opin. Neurobiol. 30, 92–99 (2015).

    Article  PubMed  CAS  Google Scholar 

  234. Morley, S. J. et al. Acetylated tubulin is essential for touch sensation in mice. eLife 5, e20813 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Yan, C. et al. Microtubule acetylation is required for mechanosensation in Drosophila. Cell Rep. 25, 1051–1065 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Akella, J. S. et al. MEC-17 is an alpha-tubulin acetyltransferase. Nature 467, 218–222 (2010). This study co-discovers, together with Shida et al. (2010), the identity of tubulin acetyltransferase.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Bounoutas, A., O’Hagan, R. & Chalfie, M. The multipurpose 15-protofilament microtubules in C. elegans have specific roles in mechanosensation. Curr. Biol. 19, 1362–1367 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Jenkins, B. V., Saunders, H. A. J., Record, H. L., Johnson-Schlitz, D. M. & Wildonger, J. Effects of mutating alpha-tubulin lysine 40 on sensory dendrite development. J. Cell Sci. 130, 4120–4131 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Pandey, U. B. et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447, 859–863 (2007).

    Article  CAS  PubMed  Google Scholar 

  240. Lee, J.-Y. et al. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J. 29, 969–980 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. d’Ydewalle, C. et al. HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat. Med. 17, 968–974 (2011).

    Article  CAS  PubMed  Google Scholar 

  242. Kim, C. et al. HDAC6 inhibitor blocks amyloid beta-induced impairment of mitochondrial transport in hippocampal neurons. PLoS One 7, e42983 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Tseng, J.-H. et al. The deacetylase HDAC6 mediates endogenous neuritic tau pathology. Cell Rep. 20, 2169–2183 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Hubbert, C. et al. HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458 (2002).

    Article  CAS  PubMed  Google Scholar 

  245. Kalinski, A. L. et al. Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition. J. Cell Biol. 218, 1871–1890 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Zhang, X. et al. HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol. Cell 27, 197–213 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Fernandez-Gonzalez, A. et al. Purkinje cell degeneration (pcd) phenotypes caused by mutations in the axotomy-induced gene, Nna1. Science 295, 1904–1906 (2002).

    Article  CAS  PubMed  Google Scholar 

  248. Rogowski, K. et al. A family of protein-deglutamylating enzymes associated with neurodegeneration. Cell 143, 564–578 (2010). This study shows that enzymes from the cytosolic carboxypeptidase family are deglutamylases. These enzymes catalyze the removal of glutamate residues from the C termini of primary and secondary peptide chains, thus removing polyglutamylation, but also generating ∆2-tubulin.

    Article  CAS  PubMed  Google Scholar 

  249. Janke, C. et al. Tubulin polyglutamylase enzymes are members of the TTL domain protein family. Science 308, 1758–1762 (2005). This study reports the discovery of tubulin glutamylases as TTL-like proteins.

    Article  CAS  PubMed  Google Scholar 

  250. Magiera, M. M. et al. Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport. EMBO J. 37, e100440 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  251. Kalinina, E. et al. A novel subfamily of mouse cytosolic carboxypeptidases. Faseb J. 21, 836–850 (2007).

    Article  CAS  PubMed  Google Scholar 

  252. Rodriguez de la Vega, M. et al. Nna1-like proteins are active metallocarboxypeptidases of a new and diverse M14 subfamily. Faseb J. 21, 851–865 (2007).

    Article  CAS  PubMed  Google Scholar 

  253. Shashi, V. et al. Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration. EMBO J. 37, e100540 (2018). The first report of defects in polyglutamylation causing a novel human neurodegenerative disorder.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  254. Sheffer, R. et al. Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy. Eur. J. Hum. Genet. 27, 1419–1426 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Karakaya, M. et al. Biallelic variant in AGTPBP1 causes infantile lower motor neuron degeneration and cerebellar atrophy. Am. J. Med. Genet. A 179, 1580–1584 (2019).

    CAS  PubMed  Google Scholar 

  256. Gilmore-Hall, S. et al. CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice. J. Cell Biol. 218, 206–219 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Bodakuntla, S. et al. Tubulin polyglutamylation is a general traffic control mechanism in hippocampal neurons. J. Cell Sci. 133, jcs241802 (2020).

    Article  CAS  PubMed  Google Scholar 

  258. Joshi, H. C. & Cleveland, D. W. Differential utilization of beta-tubulin isotypes in differentiating neurites. J. Cell Biol. 109, 663–673 (1989).

    Article  CAS  PubMed  Google Scholar 

  259. Ferreira, A. & Caceres, A. Expression of the class III beta-tubulin isotype in developing neurons in culture. J. Neurosci. Res. 32, 516–529 (1992).

    Article  CAS  PubMed  Google Scholar 

  260. Lee, M. K., Tuttle, J. B., Rebhun, L. I., Cleveland, D. W. & Frankfurter, A. The expression and posttranslational modification of a neuron-specific beta-tubulin isotype during chick embryogenesis. Cell Motil. Cytoskeleton 17, 118–132 (1990).

    Article  CAS  PubMed  Google Scholar 

  261. Katsetos, C. D. et al. Differential localization of class III, beta-tubulin isotype and calbindin-D28k defines distinct neuronal types in the developing human cerebellar cortex. J. Neuropathol. Exp. Neurol. 52, 655–666 (1993).

    Article  CAS  PubMed  Google Scholar 

  262. Moskowitz, P. F. & Oblinger, M. M. Sensory neurons selectively upregulate synthesis and transport of the beta III-tubulin protein during axonal regeneration. J. Neurosci. 15, 1545–1555 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Latremoliere, A. et al. Neuronal-specific TUBB3 is not required for normal neuronal function but is essential for timely axon regeneration. Cell Rep. 24, 1865–1879 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Deanin, G. G. & Gordon, M. W. The distribution of tyrosyltubulin ligase in brain and other tissues. Biochem. Biophys. Res. Commun. 71, 676–683 (1976).

    Article  CAS  PubMed  Google Scholar 

  265. Deanin, G. G., Thompson, W. C. & Gordon, M. W. Tyrosyltubulin ligase activity in brain, skeletal muscle, and liver of the developing chick. Dev. Biol. 57, 230–233 (1977).

    Article  CAS  PubMed  Google Scholar 

  266. Chen, C. Y. et al. Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure. Nat. Med. 24, 1225–1233 (2018).

    Article  CAS  PubMed  Google Scholar 

  267. Fonrose, X. et al. Parthenolide inhibits tubulin carboxypeptidase activity. Cancer Res. 67, 3371–3378 (2007).

    Article  CAS  PubMed  Google Scholar 

  268. Randazzo, D. et al. Persistent upregulation of the beta-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle. Hum. Mol. Genet. 28, 1117–1135 (2019).

    Article  CAS  PubMed  Google Scholar 

  269. Lewis, S. A. & Cowan, N. J. Complex regulation and functional versatility of mammalian alpha- and beta-tubulin isotypes during the differentiation of testis and muscle cells. J. Cell Biol. 106, 2023–2033 (1988).

    Article  CAS  PubMed  Google Scholar 

  270. Redemann, S. et al. C. elegans chromosomes connect to centrosomes by anchoring into the spindle network. Nat. Commun. 8, 15288 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  271. Needleman, D. J. et al. Fast microtubule dynamics in meiotic spindles measured by single molecule imaging: evidence that the spindle environment does not stabilize microtubules. Mol. Biol. Cell 21, 323–333 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Surrey, T., Nedelec, F., Leibler, S. & Karsenti, E. Physical properties determining self-organization of motors and microtubules. Science 292, 1167–1171 (2001).

    Article  CAS  PubMed  Google Scholar 

  273. Roostalu, J., Rickman, J., Thomas, C., Nedelec, F. & Surrey, T. Determinants of polar versus nematic organization in networks of dynamic microtubules and mitotic motors. Cell 175, 796–808 e714 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Honda, Y., Tsuchiya, K., Sumiyoshi, E., Haruta, N. & Sugimoto, A. Tubulin isotype substitution revealed that isotype combination modulates microtubule dynamics in C. elegans embryos. J. Cell Sci. 130, 1652–1661 (2017).

    Article  CAS  PubMed  Google Scholar 

  275. Gundersen, G. G. & Bulinski, J. C. Distribution of tyrosinated and nontyrosinated alpha-tubulin during mitosis. J. Cell Biol. 102, 1118–1126 (1986). This is the first study demonstrating the differential distribution of tyrosinated versus detyrosinated tubulin on different microtubules of the mitotic spindle.

    Article  CAS  PubMed  Google Scholar 

  276. Regnard, C., Desbruyeres, E., Denoulet, P. & Eddé, B. Tubulin polyglutamylase: isozymic variants and regulation during the cell cycle in HeLa cells. J. Cell Sci. 112, 4281–4289 (1999).

    CAS  PubMed  Google Scholar 

  277. Barisic, M., Aguiar, P., Geley, S. & Maiato, H. Kinetochore motors drive congression of peripheral polar chromosomes by overcoming random arm-ejection forces. Nat. Cell Biol. 16, 1249–1256 (2014).

    Article  CAS  PubMed  Google Scholar 

  278. Caudron, F. et al. Mutation of Ser172 in yeast beta tubulin induces defects in microtubule dynamics and cell division. PLoS One 5, e13553 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  279. Noatynska, A., Gotta, M. & Meraldi, P. Mitotic spindle (DIS)orientation and DISease: cause or consequence? J. Cell Biol. 199, 1025–1035 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Thery, M. et al. The extracellular matrix guides the orientation of the cell division axis. Nat. Cell Biol. 7, 947–953 (2005).

    Article  CAS  PubMed  Google Scholar 

  281. Busson, S., Dujardin, D., Moreau, A., Dompierre, J. & De Mey, J. R. Dynein and dynactin are localized to astral microtubules and at cortical sites in mitotic epithelial cells. Curr. Biol. 8, 541–544 (1998).

    Article  CAS  PubMed  Google Scholar 

  282. Godin, J. D. et al. Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis. Neuron 67, 392–406 (2010).

    Article  CAS  PubMed  Google Scholar 

  283. Hewitt, G. M. Meiotic drive for B-chromosomes in the primary oocytes of Myrmeleotettix maculatus (Orthopera: Acrididae). Chromosoma 56, 381–391 (1976).

    Article  CAS  PubMed  Google Scholar 

  284. Akera, T. et al. Spindle asymmetry drives non-mendelian chromosome segregation. Sci. 358, 668–672 (2017). Akera et al. demonstrate how asymmetric distribution of tyrosination in meiotic spindles drives non-Mendelian chromosome segregation in mouse oocytes. This study links tubulin PTMs to meiotic drive.

    Article  CAS  Google Scholar 

  285. Conduit, P. T., Wainman, A. & Raff, J. W. Centrosome function and assembly in animal cells. Nat. Rev. Mol. Cell Biol. 16, 611–624 (2015).

    Article  CAS  PubMed  Google Scholar 

  286. Bobinnec, Y. et al. Centriole disassembly in vivo and its effect on centrosome structure and function in vertebrate cells. J. Cell Biol. 143, 1575–1589 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Gonczy, P. & Hatzopoulos, G. N. Centriole assembly at a glance. J. Cell Sci. 132, jcs228833 (2019).

    Article  CAS  PubMed  Google Scholar 

  288. Gambarotto, D. et al. Imaging cellular ultrastructures using expansion microscopy (U-ExM). Nat. Methods 16, 71–74 (2019).

    Article  CAS  PubMed  Google Scholar 

  289. Hamel, V. et al. Identification of Chlamydomonas central core centriolar proteins reveals a role for human WDR90 in ciliogenesis. Curr. Biol. 27, 2486–2498 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Wolff, A. et al. Distribution of glutamylated alpha and beta-tubulin in mouse tissues using a specific monoclonal antibody, GT335. Eur. J. Cell Biol. 59, 425–432 (1992).

    CAS  PubMed  Google Scholar 

  291. Abal, M., Keryer, G. & Bornens, M. Centrioles resist forces applied on centrosomes during G2/M transition. Biol. Cell 97, 425–434 (2005).

    Article  CAS  PubMed  Google Scholar 

  292. Nigg, E. A. & Holland, A. J. Once and only once: mechanisms of centriole duplication and their deregulation in disease. Nat. Rev. Mol. Cell Biol. 19, 297–312 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Sanchez, I. & Dynlacht, B. D. Cilium assembly and disassembly. Nat. Cell Biol. 18, 711–717 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Eguether, T. & Hahne, M. Mixed signals from the cell’s antennae: primary cilia in cancer. EMBO Rep. 19, e46589 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  295. Rocha, C. et al. Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon. EMBO J. 33, 2247–2260 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Lewis, S. A., Gu, W. & Cowan, N. J. Free intermingling of mammalian beta-tubulin isotypes among functionally distinct microtubules. Cell 49, 539–548 (1987).

    Article  CAS  PubMed  Google Scholar 

  297. Joshi, H. C. & Cleveland, D. W. Diversity among tubulin subunits: toward what functional end? Cell Motil. Cytoskeleton 16, 159–163 (1990).

    Article  CAS  PubMed  Google Scholar 

  298. Luduena, R. F. Are tubulin isotypes functionally significant. Mol. Biol. Cell 4, 445–457 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Pratt, L. F., Okamura, S. & Cleveland, D. W. A divergent testis-specific alpha-tubulin isotype that does not contain a coded C-terminal tyrosine. Mol. Cell Biol. 7, 552–555 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  300. Rogowski, K. et al. Evolutionary divergence of enzymatic mechanisms for posttranslational polyglycylation. Cell 137, 1076–1087 (2009).

    Article  CAS  PubMed  Google Scholar 

  301. Bompard, G. et al. CSAP acts as a regulator of TTLL-mediated microtubule glutamylation. Cell Rep. 25, 2866–2877 e2865 (2018).

    Article  CAS  PubMed  Google Scholar 

  302. Regnard, C. et al. Characterisation of PGs1, a subunit of a protein complex co-purifying with tubulin polyglutamylase. J. Cell Sci. 116, 4181–4190 (2003).

    Article  CAS  PubMed  Google Scholar 

  303. Carvalho-Santos, Z., Azimzadeh, J., Pereira-Leal, J. B. & Bettencourt-Dias, M. Evolution: tracing the origins of centrioles, cilia, and flagella. J. Cell Biol. 194, 165–175 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Magiera, M. M. & Janke, C. Post-translational modifications of tubulin. Curr. Biol. 24, R351–R354 (2014).

    Article  CAS  PubMed  Google Scholar 

  305. Caporizzo, M. A., Chen, C. Y., Salomon, A. K., Margulies, K. B. & Prosser, B. L. Microtubules provide a viscoelastic resistance to myocyte motion. Biophys. J. 115, 1796–1807 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. North, B. J., Marshall, B. L., Borra, M. T., Denu, J. M. & Verdin, E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol. Cell 11, 437–444 (2003).

    Article  CAS  PubMed  Google Scholar 

  307. Adamopoulos, A. et al. Crystal structure of the tubulin tyrosine carboxypeptidase complex VASH1-SVBP. Nat. Struct. Mol. Biol. 26, 567–570 (2019).

    Article  CAS  PubMed  Google Scholar 

  308. Li, F., Hu, Y., Qi, S., Luo, X. & Yu, H. Structural basis of tubulin detyrosination by vasohibins. Nat. Struct. Mol. Biol. 26, 583–591 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  309. Liao, S. et al. Molecular basis of vasohibins-mediated detyrosination and its impact on spindle function and mitosis. Cell Res. 29, 533–547 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  310. Wang, N. et al. Structural basis of tubulin detyrosination by the vasohibin-SVBP enzyme complex. Nat. Struct. Mol. Biol. 26, 571–582 (2019).

    Article  CAS  PubMed  Google Scholar 

  311. Zhou, C., Yan, L., Zhang, W.-H. & Liu, Z. Structural basis of tubulin detyrosination by VASH2/SVBP heterodimer. Nat. Commun. 10, 3212 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  312. Ersfeld, K. et al. Characterization of the tubulin-tyrosine ligase. J. Cell Biol. 120, 725–732 (1993).

    Article  CAS  PubMed  Google Scholar 

  313. Kimura, Y. et al. Identification of tubulin deglutamylase among Caenorhabditis elegans and mammalian cytosolic carboxypeptidases (CCPs). J. Biol. Chem. 285, 22936–22941 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  314. Tort, O. et al. The cytosolic carboxypeptidases CCP2 and CCP3 catalyze posttranslational removal of acidic amino acids. Mol. Biol. Cell 25, 3017–3027 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  315. Ikegami, K. et al. TTLL7 is a mammalian beta-tubulin polyglutamylase required for growth of MAP2-positive neurites. J. Biol. Chem. 281, 30707–30716 (2006).

    Article  CAS  PubMed  Google Scholar 

  316. Ikegami, K. & Setou, M. TTLL10 can perform tubulin glycylation when co-expressed with TTLL8. FEBS Lett. 583, 1957–1963 (2009).

    Article  CAS  PubMed  Google Scholar 

  317. Huang, K., Diener, D. R. & Rosenbaum, J. L. The ubiquitin conjugation system is involved in the disassembly of cilia and flagella. J. Cell Biol. 186, 601–613 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  318. Rosas-Acosta, G., Russell, W. K., Deyrieux, A., Russell, D. H. & Wilson, V. G. A universal strategy for proteomic studies of SUMO and other ubiquitin-like modifiers. Mol. Cell Proteom. 4, 56–72 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the ANR-10-IDEX-0001–02 and the LabEx CelTisPhyBio ANR-11-LBX-0038. C.J. is supported by the Institut Curie, French National Research Agency (ANR) awards ANR-12-BSV2-0007 and ANR-17-CE13-0021, French Institut National du Cancer grants 2013-PL BIO-02-ICR-1 and 2014-PL BIO-11-ICR-1 and Fondation pour la Recherche Medicale grant DEQ20170336756. M.M.M. is supported by Fondation Vaincre Alzheimer grant FR-16055p. The authors thank L. Eshun-Wilson and E. Nogales (University of California, Berkeley, USA) for help with adapting Fig. 2c, and S. Bodakuntla, S. Gadadhar, Jijumon A.S. and M. Genova (Institut Curie), J. C. Bulinski (Columbia University, New York, USA), Q. Kimmerlin (EFS Strasbourg, France), T. Müller-Reichert (TU Dresden, Germany), M. V. Nachury (University of California, San Francisco, USA), D. Portran (Centre de Recherche en Biologie cellulaire de Montpellier, France) and M. Sirajuddin (Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India) for instructive discussions.

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Glossary

Axonemes

A tubular structure built from microtubules and associated proteins at the core of all eukaryotic cilia and flagella. In motile cilia and flagella, the axoneme consists of nine microtubule doublets arranged around a central microtubule pair, accessory proteins and axonemal dynein motors that ensure the beating of cilia. Primary cilia lack the motor protein and central-pair microtubules.

Marginal band

A microtubule coil of precisely 12 turns at the outer rim of blood platelets.

A tubules

Components of the microtubule doublets of axonemes. A tubules are generic microtubules made of 13 protofilaments.

CAP-Gly domain-containing proteins

Cytoskeleton-associated proteins (CAP) containing a glycine (Gly)-rich domain. These proteins contain a well-conserved GKNDG sequence motif that specifically recognizes EEY/F sequences, which targets them to the plus ends of tyrosinated microtubules.

+TIP complexes

A group of microtubule-interacting proteins localized to the plus ends of microtubules. For most of these proteins, plus-end localization is mediated by end-binding (EB) proteins, such as mammalian EB1, EB2 and EB3 or yeast Bim1p.

Kinetochores

Multiprotein structures associated with the centromeres of duplicated chromosomes in eukaryotic cells. Kinetochores are the docking sites for spindle microtubules to pull sister chromatids apart. Kinetochores further control correct sister chromatid attachment via checkpoints.

Ependymal cells

Glial cells lining the ventricles of the mammalian brain and the central canal of the spinal cord. Ependymal cells have multiple motile cilia, whose coordinated beating determines the direction of flow of cerebrospinal fluid. They are also called ‘ependymocytes’.

B tubules

Components of the microtubule doublets of axonemes. Partial microtubules made of ten protofilaments that partly share the wall of the A tubules.

Basal bodies

A microtubule-based multiprotein structure at the base of cilia and flagella. The core microtubule structure of the basal body, the centriole, is the same as that which constitutes the core of the centrosomes of dividing cells.

Primary cilia

A solitary microtubule-based organelle emanating from the cell surface of most mammalian cells. Primary cilia are thought to be environmental sensors and signalling hubs of the cell, and their dysfunction was linked to a variety of ciliopathies and cancers. Primary cilia contain axonemes without dynein motors and are thus non-motile.

Connecting cilia

Modified primary cilia connecting the cell body to the outer segment of photoreceptor cells in the retina.

Growth cone

Dynamic structure at the tip of a growing neurite, able to sense the environment and guide neurite outgrowth and connection. Growth cones are temporal structures in developing neurons.

Microcephaly

A medical condition in which the brain and head of patients are smaller than expected.

Purkinje cell

GABAergic neurons located in the cerebellar cortex. Purkinje cells are among the largest neurons in the brain and possess highly branched dendritic trees.

Viscoelasticity

The property of materials that exhibit both viscous and elastic characteristics when undergoing deformation.

Desmin

Muscle-specific intermediate filament assembly essential for the structural integrity and function of muscle fibres.

Astral microtubules

A microtubule population that exists only during mitosis. Astral microtubules connect the centrosomes to the cell cortex and serve to orient the mitotic spindle in the cell.

Meiotic drive

The preferential, non-Mendelian transmission of a particular allele or locus during meiosis.

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Janke, C., Magiera, M.M. The tubulin code and its role in controlling microtubule properties and functions. Nat Rev Mol Cell Biol 21, 307–326 (2020). https://doi.org/10.1038/s41580-020-0214-3

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