Skip to main content
SpringerLink
Log in

Role of tubulin acetylation in cellular functions and diseases

  • Review
  • Published:
Medical Molecular Morphology Aims and scope Submit manuscript

Abstract

Acetylation is a well-studied post-translational modification (PTM) of tubulin. Acetylated tubulin is present in the centrioles, primary cilia, and flagella, which contain long-lived stable microtubules. Tubulin acetylation plays an important role in cellular activities including cell polarity, cell migration, vesicle transport, and cell development. Cryo-electron microscopy reconstructions have revealed conformational changes in acetylated tubulin, revealing a reduction in intermonomer interactions among tubulins and an increase in microtubule elasticity. The kinetics of conformational changes in acetylated tubulin may elucidate microtubule functions in these cellular activities. Abnormal tubulin acetylation has been implicated in neurodegenerative disorders, ciliopathies, and cancers. Thus, it is important to elucidate the mechanisms underlying tubulin acetylation and its effects on cellular activity to understand these diseases and to design potential therapeutic strategies. This review discusses the cellular distribution and dynamics of acetylated tubulin and its role in regulating cellular activities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Chaaban S, Brouhard GJ (2017) A microtubule bestiary: structural diversity in tubulin polymers. Mol Biol Cell 28:2924–2931

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Amos L, Klug A (1974) Arrangement of subunits in flagellar microtubules. J Cell Sci 14:523–549

    CAS  PubMed  Google Scholar 

  3. Janke C (2014) The tubulin code: molecular components, readout mechanisms, and functions. J Cell Biol 206:461–472

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Krebs A, Goldie KN, Hoenger A (2005) Structural rearrangements in tubulin following microtubule formation. EMBO Rep 6:227–232

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Manka SW, Moores CA (2018) Microtubule structure by cryo-EM: snapshots of dynamic instability. Essays Biochem 62:737–751

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. Song Y, Brady ST (2015) Post-translational modifications of tubulin: pathways to functional diversity of microtubules. Trends Cell Biol 25:125–136

    CAS  PubMed  Google Scholar 

  8. Piperno G, LeDizet M, Chang XJ (1987) Microtubules containing acetylated alpha-tubulin in mammalian cells in culture. J Cell Biol 104:289–302

    CAS  PubMed  Google Scholar 

  9. Piperno G, Fuller MT (1985) Monoclonal antibodies specific for an acetylated form of alpha-tubulin recognize the antigen in cilia and flagella from a variety of organisms. J Cell Biol 101:2085–2094

    CAS  PubMed  Google Scholar 

  10. Palazzo A, Ackerman B, Gundersen GG (2003) Cell biology: tubulin acetylation and cell motility. Nature 421:230

    CAS  PubMed  Google Scholar 

  11. Kalebic N, Sorrentino S, Perlas E, Bolasco G, Martinez C, Heppenstall PA (2013) alphaTAT1 is the major alpha-tubulin acetyltransferase in mice. Nat Commun 4:1962

    PubMed  Google Scholar 

  12. Howes SC, Alushin GM, Shida T, Nachury MV, Nogales E (2014) Effects of tubulin acetylation and tubulin acetyltransferase binding on microtubule structure. Mol Biol Cell 25:257–266

    PubMed  PubMed Central  Google Scholar 

  13. Cueva JG, Hsin J, Huang KC, Goodman MB (2012) Posttranslational acetylation of alpha-tubulin constrains protofilament number in native microtubules. Curr Biol 22:1066–1074

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Portran D, Schaedel L, Xu Z, Thery M, Nachury MV (2017) Tubulin acetylation protects long-lived microtubules against mechanical ageing. Nat Cell Biol 19:391–398

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Eshun-Wilson L, Zhang R, Portran D, Nachury MV, Toso DB, Lohr T, Vendruscolo M, Bonomi M, Fraser JS, Nogales E (2019) Effects of α-tubulin acetylation on microtubule structure and stability. Proc Natl Acad Sci USA 116:10366–10371

    CAS  PubMed  Google Scholar 

  16. Akella JS, Wloga D, Kim J, Starostina NG, Lyons-Abbott S, Morrissette NS, Dougan ST, Kipreos ET, Gaertig J (2010) MEC-17 is an alpha-tubulin acetyltransferase. Nature 467:218–222

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Shida T, Cueva JG, Xu Z, Goodman MB, Nachury MV (2010) The major alpha-tubulin K40 acetyltransferase alphaTAT1 promotes rapid ciliogenesis and efficient mechanosensation. Proc Natl Acad Sci USA 107:21517–21522

    CAS  PubMed  Google Scholar 

  18. Kim GW, Li L, Ghorbani M, You L, Yang XJ (2013) Mice lacking alpha-tubulin acetyltransferase 1 are viable but display alpha-tubulin acetylation deficiency and dentate gyrus distortion. J Biol Chem 288:20334–20350

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Aguilar A, Becker L, Tedeschi T, Heller S, Iomini C, Nachury MV (2014) Alpha-tubulin K40 acetylation is required for contact inhibition of proliferation and cell-substrate adhesion. Mol Biol Cell 25:1854–1866

    PubMed  PubMed Central  Google Scholar 

  20. Solinger JA, Paolinelli R, Kloss H, Scorza FB, Marchesi S, Sauder U, Mitsushima D, Capuani F, Sturzenbaum SR, Cassata G (2010) The Caenorhabditis elegans Elongator complex regulates neuronal alpha-tubulin acetylation. PLoS Genet 6:e1000820

    PubMed  PubMed Central  Google Scholar 

  21. Friedman JR, Webster BM, Mastronarde DN, Verhey KJ, Voeltz GK (2010) ER sliding dynamics and ER-mitochondrial contacts occur on acetylated microtubules. J Cell Biol 190:363–375

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Taschner M, Vetter M, Lorentzen E (2012) Atomic resolution structure of human alpha-tubulin acetyltransferase bound to acetyl-CoA. Proc Natl Acad Sci USA 109:19649–19654

    CAS  PubMed  Google Scholar 

  23. Zhang Y, Ma C, Delohery T, Nasipak B, Foat BC, Bounoutas A, Bussemaker HJ, Kim SK, Chalfie M (2002) Identification of genes expressed in C. elegans touch receptor neurons. Nature 418:331–335

    CAS  PubMed  Google Scholar 

  24. Ly N, Elkhatib N, Bresteau E, Pietrement O, Khaled M, Magiera MM, Janke C, Le Cam E, Rutenberg AD, Montagnac G (2016) alphaTAT1 controls longitudinal spreading of acetylation marks from open microtubules extremities. Sci Rep 6:35624

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Coombes C, Yamamoto A, McClellan M, Reid TA, Plooster M, Luxton GW, Alper J, Howard J, Gardner MK (2016) Mechanism of microtubule lumen entry for the alpha-tubulin acetyltransferase enzyme alphaTAT1. Proc Natl Acad Sci USA 113:E7176–e7184

    CAS  PubMed  Google Scholar 

  26. Maruta H, Greer K, Rosenbaum JL (1986) The acetylation of alpha-tubulin and its relationship to the assembly and disassembly of microtubules. J Cell Biol 103:571–579

    CAS  PubMed  Google Scholar 

  27. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417:455–458

    CAS  PubMed  Google Scholar 

  28. North BJ, Marshall BL, Borra MT, Denu JM, Verdin E (2003) The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 11:437–444

    CAS  PubMed  Google Scholar 

  29. Zilberman Y, Ballestrem C, Carramusa L, Mazitschek R, Khochbin S, Bershadsky A (2009) Regulation of microtubule dynamics by inhibition of the tubulin deacetylase HDAC6. J Cell Sci 122:3531

    CAS  PubMed  Google Scholar 

  30. Selenica ML, Benner L, Housley SB, Manchec B, Lee DC, Nash KR, Kalin J, Bergman JA, Kozikowski A, Gordon MN, Morgan D (2014) Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition. Alzheimers Res Ther 6:12

    PubMed  PubMed Central  Google Scholar 

  31. Reed NA, Cai D, Blasius TL, Jih GT, Meyhofer E, Gaertig J, Verhey KJ (2006) Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol 16:2166–2172

    CAS  PubMed  Google Scholar 

  32. Dompierre JP, Godin JD, Charrin BC, Cordelieres FP, King SJ, Humbert S, Saudou F (2007) Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J Neurosci 27:3571–3583

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Alper JD, Decker F, Agana B, Howard J (2014) The motility of axonemal dynein is regulated by the tubulin code. Biophys J 107:2872–2880

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Even A, Morelli G, Broix L, Scaramuzzino C, Turchetto S, Gladwyn-Ng I, Le Bail R, Shilian M, Freeman S, Magiera MM, Jijumon AS, Krusy N, Malgrange B, Brone B, Dietrich P, Dragatsis I, Janke C, Saudou F, Weil M, Nguyen L (2019) ATAT1-enriched vesicles promote microtubule acetylation via axonal transport. Sci Adv 5:eaax2705–eaax2705

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Nakakura T, Suzuki T, Torii S, Asano-Hoshino A, Nekooki-Machida Y, Tanaka H, Arisawa K, Nishijima Y, Susa T, Okazaki T, Kiuchi Y, Hagiwara H (2017) ATAT1 is essential for regulation of homeostasis-retaining cellular responses in corticotrophs along hypothalamic-pituitary-adrenal axis. Cell Tissue Res 370:169–178

    CAS  PubMed  Google Scholar 

  36. Geeraert C, Ratier A, Pfisterer SG, Perdiz D, Cantaloube I, Rouault A, Pattingre S, Proikas-Cezanne T, Codogno P, Pous C (2010) Starvation-induced hyperacetylation of tubulin is required for the stimulation of autophagy by nutrient deprivation. J Biol Chem 285:24184–24194

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Perdiz D, Mackeh R, Pous C, Baillet A (2011) The ins and outs of tubulin acetylation: more than just a post-translational modification? Cell Signal 23:763–771

    CAS  PubMed  Google Scholar 

  38. Yang L, Zhao L, Cui L, Huang Y, Ye J, Zhang Q, Jiang X, Zhang D, Huang Y (2019) Decreased alpha-tubulin acetylation induced by an acidic environment impairs autophagosome formation and leads to rat cardiomyocyte injury. J Mol Cell Cardiol 127:143–153

    CAS  PubMed  Google Scholar 

  39. Nekooki-Machida Y, Nakakura T, Nishijima Y, Tanaka H, Arisawa K, Kiuchi Y, Miyashita T, Hagiwara H (2018) Dynamic localization of alpha-tubulin acetyltransferase ATAT1 through the cell cycle in human fibroblastic KD cells. Med Mol Morphol 51:217–226

    CAS  PubMed  Google Scholar 

  40. Chu DT, Klymkowsky MW (1989) The appearance of acetylated alpha-tubulin during early development and cellular differentiation in Xenopus. Dev Biol 136:104–117

    CAS  PubMed  Google Scholar 

  41. Nakakura T, Suzuki T, Nemoto T, Tanaka H, Asano-Hoshino A, Arisawa K, Nishijima Y, Kiuchi Y, Hagiwara H (2016) Intracellular localization of alpha-tubulin acetyltransferase ATAT1 in rat ciliated cells. Med Mol Morphol 49:133–143

    CAS  PubMed  Google Scholar 

  42. Zhang Y, Li N, Caron C, Matthias G, Hess D, Khochbin S, Matthias P (2003) HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. EMBO J 22:1168–1179

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Inoue T, Hiratsuka M, Osaki M, Oshimura M (2007) The molecular biology of mammalian SIRT proteins: SIRT2 in cell cycle regulation. Cell Cycle 6:1011–1018

    CAS  PubMed  Google Scholar 

  44. Wickström SA, Masoumi KC, Khochbin S, Fässler R, Massoumi R (2010) CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin. EMBO J 29:131–144

    PubMed  Google Scholar 

  45. Li L, Jayabal S, Ghorbani M, Legault LM, McGraw S, Watt AJ, Yang XJ (2019) ATAT1 regulates forebrain development and stress-induced tubulin hyperacetylation. Cell Mol Life Sci 76:3621–3640

    CAS  PubMed  Google Scholar 

  46. Zhang Y, Kwon S, Yamaguchi T, Cubizolles F, Rousseaux S, Kneissel M, Cao C, Li N, Cheng H-L, Chua K, Lombard D, Mizeracki A, Matthias G, Alt FW, Khochbin S, Matthias P (2008) Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol Cell Biol 28:1688–1701

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Bobrowska A, Donmez G, Weiss A, Guarente L, Bates G (2012) SIRT2 ablation has no effect on tubulin acetylation in brain, cholesterol biosynthesis or the progression of Huntington's disease phenotypes in vivo. PLoS ONE 7:e34805–e34805

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Hagiwara H, Ohwada N, Takata T (2004) Cell biology of normal and abnormal ciliogenesis in the ciliated epithelium. Int Rev Cytol 234:101–141

    PubMed  Google Scholar 

  49. Miyoshi K, Kasahara K, Miyazaki I, Asanuma M (2009) Lithium treatment elongates primary cilia in the mouse brain and in cultured cells. Biochem Biophys Res Commun 388:757–762

    CAS  PubMed  Google Scholar 

  50. Nakakura T, Asano-Hoshino A, Suzuki T, Arisawa K, Tanaka H, Sekino Y, Kiuchi Y, Kawai K, Hagiwara H (2015) The elongation of primary cilia via the acetylation of alpha-tubulin by the treatment with lithium chloride in human fibroblast KD cells. Med Mol Morphol 48:44–53

    CAS  PubMed  Google Scholar 

  51. Wang W, Brautigan DL (2008) Phosphatase inhibitor 2 promotes acetylation of tubulin in the primary cilium of human retinal epithelial cells. BMC Cell Biol 9:62

    PubMed  PubMed Central  Google Scholar 

  52. Kozminski KG, Diener DR, Rosenbaum JL (1993) High level expression of nonacetylatable alpha-tubulin in Chlamydomonas reinhardtii. Cell Motil Cytoskeleton 25:158–170

    CAS  PubMed  Google Scholar 

  53. Gaertig J, Cruz MA, Bowen J, Gu L, Pennock DG, Gorovsky MA (1995) Acetylation of lysine 40 in alpha-tubulin is not essential in Tetrahymena thermophila. J Cell Biol 129:1301–1310

    CAS  PubMed  Google Scholar 

  54. Goetz SC, Anderson KV (2010) The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11:331–344

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Loktev AV, Zhang Q, Beck JS, Searby CC, Scheetz TE, Bazan JF, Slusarski DC, Sheffield VC, Jackson PK, Nachury MV (2008) A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell 15:854–865

    CAS  PubMed  Google Scholar 

  56. Yang Y, Ran J, Liu M, Li D, Li Y, Shi X, Meng D, Pan J, Ou G, Aneja R, Sun SC, Zhou J (2014) CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6. Cell Res 24:1342–1353

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Keryer G, Pineda JR, Liot G, Kim J, Dietrich P, Benstaali C, Smith K, Cordelières FP, Spassky N, Ferrante RJ, Dragatsis I, Saudou F (2011) Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J Clin Investig 121:4372–4382

    CAS  PubMed  Google Scholar 

  58. Chang J, Baloh RH, Milbrandt J (2009) The NIMA-family kinase Nek3 regulates microtubule acetylation in neurons. J Cell Sci 122:2274–2282

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Pongrakhananon V, Saito H, Hiver S, Abe T, Shioi G, Meng W, Takeichi M (2018) CAMSAP3 maintains neuronal polarity through regulation of microtubule stability. Proc Natl Acad Sci USA 115:9750–9755

    CAS  PubMed  Google Scholar 

  60. Sudo H, Baas PW (2010) Acetylation of microtubules influences their sensitivity to severing by katanin in neurons and fibroblasts. J Neurosci 30:7215–7226

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Law BM, Spain VA, Leinster VH, Chia R, Beilina A, Cho HJ, Taymans JM, Urban MK, Sancho RM, Blanca Ramirez M, Biskup S, Baekelandt V, Cai H, Cookson MR, Berwick DC, Harvey K (2014) A direct interaction between leucine-rich repeat kinase 2 and specific beta-tubulin isoforms regulates tubulin acetylation. J Biol Chem 289:895–908

    CAS  PubMed  Google Scholar 

  62. Godena VK, Brookes-Hocking N, Moller A, Shaw G, Oswald M, Sancho RM, Miller CC, Whitworth AJ, De Vos KJ (2014) Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat Commun 5:5245

    CAS  PubMed  PubMed Central  Google Scholar 

  63. d'Ydewalle C, Krishnan J, Chiheb DM, Van Damme P, Irobi J, Kozikowski AP, Vanden Berghe P, Timmerman V, Robberecht W, Van Den Bosch L (2011) HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot–Marie–Tooth disease. Nat Med 17:968–974

    CAS  PubMed  Google Scholar 

  64. Li L, Yang XJ (2015) Tubulin acetylation: responsible enzymes, biological functions and human diseases. Cell Mol Life Sci 72:4237–4255

    CAS  PubMed  Google Scholar 

  65. Boggs AE, Vitolo MI, Whipple RA, Charpentier MS, Goloubeva OG, Ioffe OB, Tuttle KC, Slovic J, Lu Y, Mills GB, Martin SS (2015) alpha-Tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion, and invasive migration. Cancer Res 75:203–215

    CAS  PubMed  Google Scholar 

  66. Castro-Castro A, Janke C, Montagnac G, Paul-Gilloteaux P, Chavrier P (2012) ATAT1/MEC-17 acetyltransferase and HDAC6 deacetylase control a balance of acetylation of alpha-tubulin and cortactin and regulate MT1-MMP trafficking and breast tumor cell invasion. Eur J Cell Biol 91:950–960

    CAS  PubMed  Google Scholar 

  67. Lee CC, Cheng YC, Chang CY, Lin CM, Chang JY (2018) Alpha-tubulin acetyltransferase/MEC-17 regulates cancer cell migration and invasion through epithelial-mesenchymal transition suppression and cell polarity disruption. Sci Rep 8:17477

    PubMed  PubMed Central  Google Scholar 

  68. Creppe C, Malinouskaya L, Volvert ML, Gillard M, Close P, Malaise O, Laguesse S, Cornez I, Rahmouni S, Ormenese S, Belachew S, Malgrange B, Chapelle JP, Siebenlist U, Moonen G, Chariot A, Nguyen L (2009) Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin. Cell 136:551–564

    CAS  PubMed  Google Scholar 

  69. Bance B, Seetharaman S, Leduc C, Boeda B, Etienne-Manneville S (2019) Microtubule acetylation but not detyrosination promotes focal adhesion dynamics and astrocyte migration. J Cell Sci 132:jcs225805

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

    CAS  PubMed  Google Scholar 

  71. Xu Z, Schaedel L, Portran D, Aguilar A, Gaillard J, Marinkovich MP, Thery M, Nachury MV (2017) Microtubules acquire resistance from mechanical breakage through intralumenal acetylation. Science 356:328–332

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Editage (https://www.editage.jp) for English language editing.

Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Teikyo University School of Medicine, 2-11-1 Kaga Itabashi-ku, Tokyo, 173-8605, Japan

    Yoko Nekooki-Machida & Haruo Hagiwara

Authors
  1. Yoko Nekooki-Machida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haruo Hagiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yoko Nekooki-Machida or Haruo Hagiwara.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nekooki-Machida, Y., Hagiwara, H. Role of tubulin acetylation in cellular functions and diseases. Med Mol Morphol 53, 191–197 (2020). https://doi.org/10.1007/s00795-020-00260-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00795-020-00260-8

Keywords

Search

Navigation