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HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo
Open accessAbstract
Microtubules are cylindrical cytoskeletal structures found in almost all eukaryotic cell types which are involved in a great variety of cellular processes. Reversible acetylation on the epsilon-amino group of alpha-tubulin Lys40 marks stabilized microtubule structures and may contribute to regulating microtubule dynamics. Yet, the enzymes catalysing this acetylation/deacetylation have remained unidentified until recently. Here we report that beta-tubulin interacts with histone deacetylase-6 (HDAC-6) in a yeast two-hybrid assay and in vitro. We find that HDAC-6 is a micro tubule-associated protein capable of deacetylating alpha-tubulin in vivo and in vitro. HDAC-6's microtubule binding and deacetylation functions both depend on the hdac domains. Overexpression of HDAC-6 in mammalian cells leads to tubulin hypoacetylation. In contrast, inhibition of HDAC-6 function by two independent mechanisms--pharmacological (HDAC inhibitors) or genetic (targeted inactivation of HDAC-6 in embryonic stem cells)--leads to hyperacetylation of tubulin and microtubules. Taken together, our data provide evidence that HDAC-6 might act as a dual deacetylase for tubulin and histones, and suggest the possibility that acetylated non-histone proteins might represent novel targets for pharmacological therapy by HDAC inhibitors.
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“the class IIb isozyme, HDAC6, has been associated with deacetylation of several cytosolic substrates including a -tubulin and p53 (Hubbert et al., 2002; Zhang et al., 2003; Ryu et al., 2017).”
From Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase (2018) · cites this paper as Zhang et al., 2003
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BackgroundInfluentialShepard, B. D., Joseph, R. A., Kannarkat, G. T., Rutledge, T. W., Tuma, D. J., & Tuma, P. L. (2008) · Hepatology · doi:10.1002/hep.22481 · Cited by 35
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Leech, S. H., Evans, C. A., Shaw, L., Wong, C. H., Connolly, J., Griffiths, J. R., Whetton, A. D., & Corfe, B. M. (2008) · PROTEOMICS · doi:10.1002/pmic.200700404 · Cited by 34
“Two reports highlight the role of acetylation in the regulation of microtubule function [19, 20], and show that atubulin is acetylated at K40.”
BackgroundInfluentialWu, Y.-W., Hsu, K., Lee, H., Huang, T., Lin, T. E., Chen, Y., Sung, T.-Y., Liou, J., Hwang‐Verslues, W. W., Pan, S., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00205 · Cited by 34
Laschanzky, R. S., Humphrey, L., Ma, J.-Y., Smith, L., Enke, T., Shukla, S., Dasgupta, A., Singh, P., Howell, G., Brattain, M., et al. (2019) · Cancers · doi:10.3390/cancers11091327 · Cited by 34
“Therefore, the effects of ACY-1215 on acetylation of α-tubulin, an established substrate of HDAC6 [37], were assessed by Western blotting to determine an appropriate dose of the drug.”
MethodDevipriya, B., & Kumaradhas, P. (2013) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2013.05.002 · Cited by 34
HDAC6 deacetylates alpha tubulin in sperm and modulates sperm motility in Holtzman rat
Parab, S., Shetty, O. A., Gaonkar, R., Balasinor, N., Khole, V. V., & Parte, P. P. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-2039-x · Cited by 34
HDAC6 as a potential therapeutic target for peripheral nerve disorders
Prior, R. C., Helleputte, L. V., Klingl, Y. E., & Bosch, L. V. D. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1541235 · Cited by 35
Hüber, D., Geisler, S., Monecke, S., & Hoyer‐Fender, S. (2008) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2007.10.004 · Cited by 33
Singh, H., Wray, N. H., Schappi, J. M., & Rasenick, M. M. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0016-x · Cited by 34
“HDAC6 associates with microtubules ( α and β tubulin heterodimers) [6] and deacety-lates α -tubulin [17, 18], increasing dynamic instability of microtubules [19].”
RetractedDesign and Synthesis of Cyclopeptide Analogues of the Potent Histone Deacetylase Inhibitor FR235222
Gomez‐Paloma, L., Bruno, I., Cini, E., Khochbin, S., Rodriquez, M., Taddei, M., Terracciano, S., & Sadoul, K. (2007) · ChemMedChem · doi:10.1002/cmdc.200700095 · Cited by 33
Roos, A., Kollipara, L., Buchkremer, S., Labisch, T., Brauers, E., Gatz, C., Lentz, C., Gerardo‐Nava, J., Weis, J., & Zahedi, R. P. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9456-z · Cited by 33
“disease progression [54], interacts with and deacetylates tubulin and microtubules [55], we aimed to study protein levels of this protein and detected increased levels upon depletion of cellular”
BackgroundSixto‐López, Y., Bello, M., Rodríguez-Fonseca, R. A., Rosales‐Hernández, M. C., Martínez‐Archundia, M., Gómez-Vidal, J. A., & Correa‐Basurto, J. (2016) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2016.1231084 · Cited by 31
“…DD1-HDAC6 and DD2HDAC6 domains are not totally clear since some studies have indicated that both are important for tubulin deacetylase activity (Zhang et al., 2003, 2006), while others have shown that the activity could only be attributed to DD2-HDAC6, where Tubacin (TBC) exert its inhibitory…”
BackgroundVent-Schmidt, R. Y. J., Wen, R. H., Zong, Z., Chiu, C. N., Tam, B. M., May, C. G., & Moritz, O. L. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1647-16.2016 · Cited by 36
“Because histone deacetylases can also alter the acetylation of non-nuclear proteins, we also examined tubulin acetylation by a similar assay, which is influenced by the activity of HDAC6 and may be linked to alterations in protein degradation pathways (Hubbert et al., 2002; Zhang et al., 2003; Pandey et al., 2007).”
MethodPorter, N. J., Shen, S., Bařinka, C., Kozikowski, A. P., & Christianson, D. W. (2018) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.8b00487 · Cited by 33
Molecular Mechanisms Underlying Sensory-Motor Circuit Dysfunction in SMA
Shorrock, H. K., Gillingwater, T. H., & Groen, E. J. N. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00059 · Cited by 32
Effects of downregulated HDAC6 expression on the proliferation of lung cancer cells
Kamemura, K., Ito, A., Shimazu, T., Matsuyama, A., Maeda, S., Yao, T., Horinouchi, S., Khochbin, S., & Yoshida, M. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.06.092 · Cited by 32
“Histone deacetylase 6 (HDAC6) has been identified as a cytoplasmic deacetylase that associates with microtubules (MTs) and deacetylates a-tubulin [1–3].”
BackgroundMultiple tubulin forms in ciliated protozoan Tetrahymena and Paramecium species
Libusová, L., & Dráber, P. (2006) · PROTOPLASMA · doi:10.1007/s00709-005-0152-0 · Cited by 32
“On the other hand, � -tubulin acetylation seems to be redundant in Chlamydomonas reinhardtii and maybe even in mammalian cells (Kozminski et al. 1993, Zhang et al. 2003 ).”
BackgroundDeacetylation of Transcription Factors in Carcinogenesis
Hałasa, M., Adamczuk, K., Adamczuk, G., Afshan, S., Stepulak, A., Cybulski, M., & Wawruszak, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111810 · Cited by 32
“HDACs also affect signaling mediators, including phosphatase and tensin homolog (PTEN), signal transducer and activator of transcription 3 (STAT3) [19,20], protein kinase B (Akt) [21], and β-catenin [22], as well as other nuclear proteins like Ku70 [23] and structural proteins such as α-tubulin [24].”
BackgroundZampar, G. G., Chesta, M. E., Carbajal, A., Chanaday, N. L., Díaz, N. M., Casale, C. H., & Arce, C. A. (2009) · Biochemical Journal · doi:10.1042/bj20082410 · Cited by 31
Singh, A. P., Cummings, C. A., Mishina, Y. M., & Archer, T. (2013) · Biology of Reproduction · doi:10.1095/biolreprod.112.107284 · Cited by 34
“HDAC6 is a member of the zinc-dependent HDACs [46, 47] that is localized in cytoplasm and selectively deacetylates alpha-tubulin and HSP90 [38, 48–54].”
BackgroundTough, D. F., Lewis, H. D., Rioja, I., Lindon, M. J., & Prinjha, R. K. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12848 · Cited by 30
“Notwithstanding the nomenclature, several sirtuins do function as HDACs, while at least one HDAC, HDAC6, appears to be almost exclusively localized to the cytoplasm and may not deacetylate histones in vivo (Verdel et al., 2000; Zhang et al., 2003; Martinez-Redondo and Vaquero, 2013).”
BackgroundHaakenson, J., & Zhang, X. M. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14059514 · Cited by 31
“Overexpression of HDAC6 leads to tubulin hypoacetylation and thus greater cell motility [76].”
BackgroundCatalano, M. G., Pugliese, M., Gallo, M., Brignardello, E., Milla, P., Orlandi, F., Limone, P. P., Arvat, E., Boccuzzi, G., & Piovesan, A. (2016) · International Journal of Endocrinology · doi:10.1155/2016/2930414 · Cited by 31
“Besides histones and other non-histone proteins, αtubulin is also a substrate of histone deacetylases [27].”
BackgroundHsieh, T., Hsu, C., Wu, C., Wang, S.-H., Yeh, C.-H., Cheng, K., & Tsai, E. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114500 · Cited by 30
Bonezzi, K., Belotti, D., North, B. J., Ghilardi, C., Borsotti, P., Resovi, A., Ubezio, P., Riva, A., Giavazzi, R., Verdin, E. M., et al. (2012) · Neoplasia · doi:10.1593/neo.12728 · Cited by 30
Singh, B. N., Zhou, H., Li, J., Tipton, T., Wang, B., Shao, G., Gilbert, E. N., Li, Q., & Jiang, S. (2011) · Future Oncology · doi:10.2217/fon.11.124 · Cited by 30
“reported that HDAC6 is capable of interacting with purified tubulin and microtubules in vitro and HDAC6 colocalizes with microtubules in NIH-3T3 cells [98].”
BackgroundYu, J., Ma, M., Ma, Z., & Fu, J. (2016) · Oncotarget · doi:10.18632/oncotarget.10591 · Cited by 30
“Acetylation of α-tubulin at Lys40 stabilizes microtubule structures [12, 38–41].”
Role of HDAC3-miRNA-CAGE Network in Anti-Cancer Drug-Resistance
Kwon, Y., Kim, Y., Jung, H. S., & Jeoung, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010051 · Cited by 29
“HDAC6 can interact with beta tubulin in yeast two-hybrid assays and deacetylate tubulin [56].”
BackgroundDemyanenko, S. V., Berezhnaya, E. V., Neginskaya, M. A., Rodkin, S., Dzreyan, V., & Pitinova, M. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.29266 · Cited by 29
“Acetylation of α‐tubulin increase microtubule stability and is necessary for axonal elongation and cytoskeletal reorganization during regeneration after ischemia.(33) In our study, the decreased activity of HDAC6 restores the level of acetylation of α‐tubulin in the early poststroke recovery period, reduces apoptosis…”
BackgroundInfluentialHistone Deacetylase 6 and the Disease Mechanisms of α-Synucleinopathies
Lemos, M., & Stefanova, N. (2020) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2020.586453 · Cited by 29
“Such properties allow HDAC6 to interact mainly with cytoplasmic substrates, with particular functions in cellular signaling systems involving not only acetylation but also ubiquitination of proteins and consequent protein degradation (Zhang et al., 2003; Lee et al., 2010).”
BackgroundPineau, J., Pinon, L., Mesdjian, O., Fattaccioli, J., Lennon‐Duménil, A., & Pierobon, P. (2022) · eLife · doi:10.7554/elife.78330 · Cited by 29
Metadata
- Authors
- Zhang, Y., Li, N., Caron, C., Matthias, G., Hess, D., Khochbin, S., & Matthias, P.
- Affiliations
- Friedrich Miescher Institute (CH)
- Inserm (FR)
- Corresponding author
- Matthias, Patrick
- Venue
- The EMBO Journal
- Published
- 2003-03-03
- Volume
- 22
- Issue
- 5
- Pages
- 1168-1179
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC150348
- OpenAlex
- W1979832500
- Cited by
- 740
- References
- 38
- Citations by year
- 2026: 26 · 2025: 20 · 2024: 27 · 2023: 37 · 2022: 24 · 2021: 29 · 2020: 35 · 2019: 29 · 2018: 32 · 2017: 22 · 2016: 39 · 2015: 35 · 2014: 26 · 2013: 45 · 2012: 41
- FWCI
- 9.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Harvard University
- University of California, San Francisco
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- histone deacetylase, tubulin deacetylation, alpha-tubulin, beta-tubulin, microtubules, tubulin acetylation, microtubule dynamics, histone deacetylase inhibitors, non-histone protein acetylation, cytoskeleton
- MeSH terms
- Histone Deacetylase 6, Acetylation, Animals, Cattle, Chromatography, High Pressure Liquid, Embryo, Mammalian, Histone Deacetylases, Humans, Kidney, Microtubules, Peptides, Protein Binding, Stem Cells, Tubulin, 3T3 Cells, Paclitaxel, Protein Structure, Tertiary, Two-Hybrid System Techniques, Mice
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