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Mice Lacking Histone Deacetylase 6 Have Hyperacetylated Tubulin but Are Viable and Develop Normally
Open accessAbstract
Posttranslational modifications play important roles in regulating protein structure and function. Histone deacetylase 6 (HDAC6) is a mostly cytoplasmic class II HDAC, which has a unique structure with two catalytic domains and a domain binding ubiquitin with high affinity. This enzyme was recently identified as a multisubstrate protein deacetylase that can act on acetylated histone tails, alpha-tubulin and Hsp90. To investigate the in vivo functions of HDAC6 and the relevance of tubulin acetylation/deacetylation, we targeted the HDAC6 gene by homologous recombination in embryonic stem cells and generated knockout mice. HDAC6-deficient mice are viable and fertile and show hyperacetylated tubulin in most tissues. The highest level of expression of HDAC6 is seen in the testis, yet development and function of this organ are normal in the absence of HDAC6. Likewise, lymphoid development is normal, but the immune response is moderately affected. Furthermore, the lack of HDAC6 results in a small increase in cancellous bone mineral density, indicating that this deacetylase plays a minor role in bone biology. HDAC6-deficient mouse embryonic fibroblasts show apparently normal microtubule organization and stability and also show increased Hsp90 acetylation correlating with impaired Hsp90 function. Collectively, these data demonstrate that mice survive well without HDAC6 and that tubulin hyperacetylation is not detrimental to normal mammalian development.
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“HDAC6, a tubulin deacetylase [24].”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [32]
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BackgroundRegulatory T cells in the treatment of disease
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Self-citationHistone Deacetylase 6 and Heat Shock Protein 90 Control the Functions of Foxp3 + T-Regulatory Cells
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“Importantly, HDAC6 appears to be dispensable in the normal mouse physiology and development (Zhang et al., 2008), as HDAC6 knockout mice are viable and healthy and do not show any malignant predispositions.”
BackgroundHalili, M. A., Andrews, M. R., Labzin, L. I., Schroder, K., Matthias, G., Cao, C., Lovelace, E., Reid, R. C., Le, G. T., Hume, D. A., et al. (2010) · Journal of Leukocyte Biology · doi:10.1189/jlb.0509363 · Cited by 186
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BackgroundSelf-citationCilium structure, assembly, and disassembly regulated by the cytoskeleton
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Yee, A. J., Bensinger, W., Supko, J. G., Voorhees, P. M., Berdeja, J. G., Richardson, P. G. G., Libby, E. N., Wallace, E. E., Birrer, N., Burke, J. N., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30375-8 · Cited by 205
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“The HDAC6 knockout mouse lacks ciliary phenotypes (Zhang et al. 2008), but the loss of HDAC6 could be covered by SIRT2.”
BackgroundBergman, J. A., Woan, K. V., Perez-Villarroel, P., Villagra, A., Sotomayor, E. M., & Kozikowski, A. P. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm301098e · Cited by 200
From signaling pathways to microtubule dynamics: the key players
Etienne‐Manneville, S. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.11.008 · Cited by 171
“In agreement, the tubulin deacetylase HDAC6-deficient mice show hyperacetylated tubulin in most tissues but develop normally [37].”
BackgroundMechanisms of Oocyte Maturation and Related Epigenetic Regulation
He, M., Zhang, T., Yang, Y., & Wang, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.654028 · Cited by 185
“However, HDAC6 KO mice are viable and fertile and presented no major observable phenotype (Zhang et al., 2008).”
BackgroundComprehensive lysine acetylomes emerging from bacteria to humans
Kim, G.-W., & Yang, X. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.10.001 · Cited by 167
Jochems, J., Boulden, J., Lee, B. G., Blendy, J. A., Jarpe, M. B., Mazitschek, R., van Duzer, J. H., Jones, S. S., & Berton, O. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.207 · Cited by 175
“In contrast to class I isoforms, the loss of function of HDAC6 does not produce toxicity, apoptosis, or major neurodevelopmental defects in rodents (Govindarajan et al, 2012; Haberland et al, 2009; Zhang et al, 2008).”
Post-translational modifications of Hsp90 and translating the chaperone code
Backe, S. J., Sager, R., Woodford, M. R., Makedon, A. M., & Mollapour, M. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev120.011833 · Cited by 208
Knox, T., Sahakian, E., Banik, D., Hadley, M., Palmer, E., Noonepalle, S., Kim, J., Powers, J., Gracia-Hernandez, M., Oliveira, V., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-42237-3 · Cited by 170
Tau – an inhibitor of deacetylase HDAC6 function
Perez, M., Santa‐Maria, I., De Barreda, E. G., Zhu, X., Cuadros, R., Cabrero, J. R., Sanchez‐Madrid, F., Dawson, H. N., Vitek, M. P., Perry, G., et al. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06102.x · Cited by 182
“However, while HDAC6 knockout mice have hyperacetylated tubulin, they are viable and develop normally, without neurological abnormalities (Zhang et al. 2008).”
BackgroundChromatin Remodeling in Cardiovascular Development and Physiology
Han, P., Hang, C. T., Yang, J., & Chang, C. (2011) · Circulation Research · doi:10.1161/circresaha.110.224287 · Cited by 168
Feig, J. E., Shang, Y., Rotllán, N., Vengrenyuk, Y., Wu, C., Shamir, R., Pineda‐Torra, I., Fernandez-Hernando, C. F., Fisher, E. A. A., & Garabedian, M. J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028534 · Cited by 151
“Although HDAC7 mice are embryonic lethal [27], HADC6 deficient mice are viable and fertile [28], and it will be interesting to see in future studies if regression of atherosclerosis is”
Brunden, K. R., Yao, Y., Potuzak, J. S., Ferrer, N. I., Ballatore, C., James, M. J., Hogan, A. L., Trojanowski, J. Q., Smith, A. B., & Lee, V. M. ‐. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.12.002 · Cited by 159
“In fact, a recent study demonstrated that immunoprecipitation of acetyl-tubulin from mouse brain homogenates resulted in the capture of essentially all of the α-tubulin, indicating that there was virtually no α-tubulin that was deacetylated [49].”
BackgroundResultInfluentialLi, Z., & Zhu, W. (2014) · International Journal of Biological Sciences · doi:10.7150/ijbs.9067 · Cited by 164
“Overexpression of HDAC6 promotes cell mobility, but deletion of HDAC6 has no effect on normal development and disease progression in mice model [162, 163].”
BackgroundThe Tale of Protein Lysine Acetylation in the Cytoplasm
Sadoul, K., Wang, J., Diagouraga, B., & Khochbin, S. (2010) · BioMed Research International · doi:10.1155/2011/970382 · Cited by 148
“The reason for this may come from the fact that the expression of nonacetylatable α-tubulin does not result in any obvious phenotype [104–106], nor does hyperacetylation following KO of HDAC6 [107].”
BackgroundSelf-citationCell cycle progression by the repression of primary cilia formation in proliferating cells
Goto, H., Inoko, A., & Inagaki, M. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1302-8 · Cited by 157
“HDAC6 knockout mice showed hyperacetylated tubulin in most tissues, but did not reveal apparent phenotypes that would be expected to result from aberrant ciliary formation [71].”
Tubulin Post-Translational Modifications and Microtubule Dynamics
Włoga, D., Joachimiak, E., & Fabczak, H. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102207 · Cited by 167
“elegans known as Mec-17) is the main, if not the only, acetyltransferase for K40 [11,12], and the reverse reaction is catalyzed by the deacetylases: Sirt2 (Sirtuin type 2) [13] or histone deacetylase HDAC6 [14], which is the major tubulin deacetylases in vivo [15].”
BackgroundHistone Deacetylases in Bone Development and Skeletal Disorders
Bradley, E. W., Shull, L. C., van Wijnen, A. J., McGee‐Lawrence, M. E., & Westendorf, J. J. (2015) · Physiological Reviews · doi:10.1152/physrev.00004.2015 · Cited by 163
Espallergues, J., Teegarden, S. L., Veerakumar, A., Boulden, J., Challis, C., Jochems, J., Chan, M., Petersen, T. L., Deneris, E. S., Matthias, P., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5634-11.2012 · Cited by 151
“To generate a mouse line with a selective inactivation of the HDAC6 gene in serotonin neurons, male BAC transgenic Pet1-Cre mice (Scott et al., 2005) were crossed to flHDAC6 females in which a portion of HDAC6 gene (exons 8 –10) is floxed (Zhang et al., 2008).”
BackgroundMethodResultInfluentialSelf-citationBobrowska, A., Dönmez, G., Weiss, A., Guarente, L., & Bates, G. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034805 · Cited by 131
“Consistent with this, previous studies could not detect changes in the levels of acetylated tubulin in mouse embryonic fibroblasts derived from Sirt2KO mice [41].”
ResultMIM and Cortactin Antagonism Regulates Ciliogenesis and Hedgehog Signaling
Bershteyn, M., Atwood, S. X., Woo, W., Covington, M. L., & Oro, A. E. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.07.009 · Cited by 147
“However, another study found that HDAC6 mutant mice were viable and had normal cilia (Zhang et al., 2008), prompting us to ask whether inhibition of HDAC6 could prevent cilia disassembly in MIM KD cells.”
BackgroundCheng, F., Lienlaf, M., Perez-Villarroel, P., Wang, H.-W., Lee, C., Woan, K., Woods, D., Knox, T., Bergman, J., Pinilla-Ibarz, J., et al. (2014) · Molecular Immunology · doi:10.1016/j.molimm.2014.02.019 · Cited by 140
“Second, similar results were obtained in peritoneal elicited macrophages (PEM) and dendritic cells (DC) isolated from HDAC6 knock out (HDAC6 KO) mice(Zhang et al., 2008).”
InfluentialLee, J., Kapur, M., Li, M., Choi, M., Choi, S., Kim, H.-J., Kim, I., Lee, E. J., Taylor, J. P., & Yao, T. (2014) · Journal of Cell Science · doi:10.1242/jcs.157321 · Cited by 134
Histone Deacetylase Inhibitors in Cell Pluripotency, Differentiation, and Reprogramming
Kretsovali, A., Hadjimichael, C., & Charmpilas, N. (2012) · Stem Cells International · doi:10.1155/2012/184154 · Cited by 129
“Members of the HDAC class IIb group (HDAC 6, 10) regulate cytoskeletal dynamics by controlling the acetylation of cytoskeletal proteins such as tubulin [32].”
BackgroundHistone deacetylases and epigenetic therapies of hematological malignancies
Mercurio, C., Minucci, S., & Pelicci, P. G. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.02.010 · Cited by 125
Ai, J., Wang, Y., Dar, J. A., Liu, J., Liu, L., Nelson, J. B., & Wang, Z. (2009) · Molecular Endocrinology · doi:10.1210/me.2009-0188 · Cited by 126
Loss of Deacetylation Activity of Hdac6 Affects Emotional Behavior in Mice
Fukada, M., Hanai, A., Nakayama, A., Suzuki, T., Miyata, N., Rodriguiz, R. M., Wetsel, W. C., Yao, T., & Kawaguchi, Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030924 · Cited by 122
“Hdac6-deficient mice show emotional abnormalities Hdac6-deficient (KO) mice are viable and fertile, and develop normally, regardless of the hyperacetylation of a-tubulin in most tissues [5].”
BackgroundHDAC signaling in neuronal development and axon regeneration
Cho, Y., & Cavalli, V. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.03.008 · Cited by 141
Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production
Wang, B., Rao, Y.-H., Inoue, M., Hao, R., Lai, C.-H., Chen, D. J., McDonald, S. L., Choi, M.-C., Wang, Q., Shinohara, M. L., et al. (2014) · Nature Communications · doi:10.1038/ncomms4479 · Cited by 127
Development and Therapeutic Implications of Selective Histone Deacetylase 6 Inhibitors
Kalin, J. H., & Bergman, J. A. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm4001659 · Cited by 131
Ageta‐Ishihara, N., Miyata, T., Ohshima, C., Watanabe, M., Sato, Y., Hamamura, Y., Higashiyama, T., Mazitschek, R., Bito, H., & Kinoshita, M. (2013) · Nature Communications · doi:10.1038/ncomms3532 · Cited by 130
Cardiac HDAC6 catalytic activity is induced in response to chronic hypertension
Lemon, D. D., Horn, T. R., Cavasin, M. A., Jeong, M. Y., Haubold, K. W., Long, C. S., Irwin, D. C., McCune, S. A., Chung, E., Leinwand, L. A., et al. (2011) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2011.04.005 · Cited by 114
“In this regard, HDAC6 knockout mice are viable and fertile, and thus assessment of the response of these mice to increased ventricular afterload should be particularly enlightening [54].”
Razidlo, D. F., Whitney, T. J., Casper, M. E., McGee‐Lawrence, M. E., Stensgard, B. A., Li, X., Secreto, F. J., Knutson, S. K., Hiebert, S. W., & Westendorf, J. J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011492 · Cited by 113
“Hdac6-deficiency modestly enhanced trabecular bone formation [15].”
BackgroundGodmann, M., Lambrot, R., & Kimmins, S. (2009) · Microscopy Research and Technique · doi:10.1002/jemt.20715 · Cited by 113
“Interestingly, genetic ablation of Hdac6, which shows the highest expression in the mouse testis, does not affect spermatogenesis as Hdac6 null mice are viable with normal fertility (Zhang et al., 2008).”
BackgroundYang, K., Wu, H., Zhang, Z., Leisten, E. D., Nie, X., Liu, B., Wen, Z., Zhang, J., Cunningham, M. D., & Tang, W. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00046 · Cited by 124
CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6
Yang, Y., Ran, J., Liu, M., Li, D., Li, Y., Shi, X., Meng, D., Pan, J., Ou, G., Aneja, R., et al. (2014) · Cell Research · doi:10.1038/cr.2014.136 · Cited by 122
Histone deacetylases: salesmen and customers in the post‐translational modification market
Brandl, A., Heinzel, T., & Krämer, O. H. (2009) · Biology of the Cell · doi:10.1042/bc20080158 · Cited by 109
The Biology of HDAC in Cancer: The Nuclear and Epigenetic Components
Hagelkrüys, A., Sawicka, A., Rennmayr, M., & Seiser, C. (2011) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-21631-2_2 · Cited by 114
Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition
Kalinski, A. L., Kar, A. N., Craver, J., Tosolini, A. P., Sleigh, J. N., Lee, S. J., Hawthorne, A. L., Brito‐Vargas, P., Miller-Randolph, S., Passino, R., et al. (2019) · The Journal of Cell Biology · doi:10.1083/jcb.201702187 · Cited by 119
Bobrowska, A., Paganetti, P., Matthias, P., & Bates, G. P. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020696 · Cited by 112
“It has been previously reported that the Hdac6KO line of mice used in this study, has elevated levels of acetylated tubulin in peripheral tissue but not in brain [36].”
BackgroundMethodResultInfluentialSelf-citationGenetic dissection of histone deacetylase requirement in tumor cells
Haberland, M., Johnson, A., Mokalled, M. H., Montgomery, R. L., & Olson, E. N. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903139106 · Cited by 109
Histone deacetylases in skeletal development and bone mass maintenance
McGee‐Lawrence, M. E., & Westendorf, J. J. (2010) · Gene · doi:10.1016/j.gene.2010.12.003 · Cited by 113
“Germline Hdac6 deletion modestly increases trabecular bone mineral density via unknown mechanisms (Zhang et al., 2008).”
BackgroundHDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer
Fukumoto, T., Fatkhutdinov, N., Zundell, J. A., Tcyganov, E. N., Nacarelli, T., Karakashev, S. V., Wu, S., Liu, Q., Gabrilovich, D. I., & Zhang, R. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-1302 · Cited by 127
“Notably, the complete genetic knockout of HDAC6 does not impair normal cell function (16).”
BackgroundThe role of microRNAs in bone remodeling
Jing, D., Hao, J., Shen, Y., Tang, G., Li, M., Huang, S.-H., & Zhao, Z. (2015) · International Journal of Oral Science · doi:10.1038/ijos.2015.22 · Cited by 108
Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models
Choi, H., Kim, H. J., Yang, J., Chae, S., Lee, W., Chung, S., Kim, J., Choi, H., Song, H., Lee, C. K., et al. (2019) · Aging Cell · doi:10.1111/acel.13081 · Cited by 124
“In HDAC6 KO MEFs, the basal levels of acetyl-αtubulin were highly increased as previously reported (Zhang et al., 2008) and CKD-504 did not affect the acetylation levels of both α-tubulin and histone.”
Background
Metadata
- Authors
- 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, F. W., Khochbin, S., & Matthias, P.
- Affiliations
- Friedrich Miescher Institute (CH)
- Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, P.O. Box 2543, Maulbeerstrasse 66, 4058 Basel, Switzerland
- Inserm (FR)
- Novartis (Switzerland) (CH)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Matthias, Patrick
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2008-03-01
- Volume
- 28
- Issue
- 5
- Pages
- 1688-1701
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2258784
- OpenAlex
- W2162787110
- Cited by
- 559
- References
- 0
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 18 · 2023: 24 · 2022: 37 · 2021: 35 · 2020: 47 · 2019: 32 · 2018: 27 · 2017: 38 · 2016: 24 · 2015: 28 · 2014: 32 · 2013: 33 · 2012: 39
- FWCI
- 13.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Ellison Medical Foundation
- Dalhousie University
- Université de Fribourg
- Institut National Du Cancer
- 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
- HDAC6, tubulin acetylation, tubulin deacetylation, alpha-tubulin, HSP90 acetylation, testicular development, lymphoid development, immune response, bone mineral density, microtubule organization, embryonic fibroblasts, post-translational modification, ubiquitin binding
- MeSH terms
- Histone Deacetylase 6, Acetylation, Animals, Cells, Cultured, Crosses, Genetic, Embryo, Mammalian, Female, Fetal Viability, Fibroblasts, Histone Deacetylases, Homozygote, Immunohistochemistry, Male, Mice, Inbred C57BL, Precipitin Tests, Pregnancy, Receptors, Glucocorticoid, Recombination, Genetic, Sperm Count, Spermatogenesis, Testis, Transfection, Tubulin, Absorptiometry, Photon, Bone Density, Gene Deletion, Genes, Reporter, Mice, Knockout, HSP90 Heat-Shock Proteins, Fluorescent Antibody Technique, Indirect, NIH 3T3 Cells, Embryonic Development, Luciferases, Renilla, Mice, Embryonic Stem Cells
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