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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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“a-Tubulin is a major target of HDAC6 deacetylation (50).”
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“tubulin and HSP90, at least in testis and spleen [27], a more recent report shows neurodegeneration in HDAC6 depleted mice and flies, which is accompanied by the accumulation of ubiquitinated proteins due to impaired autophagy [28] generally reminiscent of human disease.”
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Role of tubulin acetylation in cellular functions and diseases
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“Similarly, normal development was observed in HDAC6-knockout mice despite the hyperacetylation of α-tubulin in most cells [46].”
BackgroundHdac6 regulates Tip60-p400 function in stem cells
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“Furthermore, Hdac6 KD ESCs had a small but reproducible decrease in proliferation rate, while Tip60 KD caused a somewhat more severe proliferation defect (Figure 7B), consistent with previous studies (Zhang et al., 2003; Fazzio et al., 2008a).”
BackgroundResultFunction of Histone Deacetylase 6 as a Cofactor of Nuclear Receptor Coregulator LCoR
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Influenza virus uses transportin 1 for vRNP debundling during cell entry
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HDAC6 controls the kinetics of platelet activation
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“The widespread roles of HDAC6 are manifested in impaired immune response, bone development, and glucocorticoid receptor translocation as well as abnormal emotional behaviors observed in HDAC6 knockout mice (Zhang et al., 2008; Fukada et al., 2012).”
BackgroundSelf-citationHDAC4 integrates PTH and sympathetic signaling in osteoblasts
Obri, A., Makinistoglu, M. P., Zhang, H., & Karsenty, G. (2014) · The Journal of Cell Biology · doi:10.1083/jcb.201403138 · Cited by 60
“It was also demonstrated that overexpression of HDAC6 results in the chemotactic movement of the cells which is a process dependent on the microtubules (Zhang et al. 2008).”
BackgroundTargeting Histone Deacetylases in Idiopathic Pulmonary Fibrosis: A Future Therapeutic Option
Korfei, M., Mahavadi, P., & Guenther, A. (2022) · Cells · doi:10.3390/cells11101626 · Cited by 66
“Although α-tubulin is dramatically hyperacetylated in multiple tissues of Hdac6(−/−) mice, the normal phenotype of these mice indicates that this is not detrimental to normal development [216].”
BackgroundTargeting histone deacetyalses in the treatment of B- and T-cell malignancies
Zain, J. M., & O’Connor, O. A. (2010) · Investigational New Drugs · doi:10.1007/s10637-010-9591-3 · Cited by 65
“Interestingly, mice knocked out for HDAC6 show hyperacetylated tubulin in most tissues but remain viable and fertile with normal lymphoid development [33] This linkage between inhibition of an HDAC and the proteasome pathway has now raised a strong mechanistic rational for the combination of these agents in the clinic…”
BackgroundHDAC6 inhibition promotes α-tubulin acetylation and ameliorates CMT2A peripheral neuropathy in mice
Picci, C., Wong, V. S. C., Costa, C. J., McKinnon, M. C., Goldberg, D. C., Swift, M. L., Alam, N. M., Prusky, G. T., Shen, S., Kozikowski, A. P., et al. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113281 · Cited by 64
Protein Quality Control During Erythropoiesis and Hemoglobin Synthesis
Khandros, E., & Weiss, M. J. (2010) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2010.08.013 · Cited by 61
Histone deacetylase 6 inhibition restores leptin sensitivity and reduces obesity
Çakır, I., Hadley, C. K., Pan, P. L., Bagchi, R. A., Ghamari‐Langroudi, M., Porter, D. T., Wang, Q., Litt, M. J., Jana, S., Hagen, S. E., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-021-00515-3 · Cited by 80
Lysine Acetylation and Deacetylation in Brain Development and Neuropathies
Tapias, A., & Wang, Z. (2017) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2016.09.002 · Cited by 69
“Similarly, Hdac9 and Hdac6 knockout mice show no obvious neural phenotypes [96,97].”
BackgroundPedersen, L. B., Schrøder, J. M., Satir, P., & Christensen, S. T. (2012) · Comprehensive physiology · doi:10.1002/cphy.c110043 · Cited by 69
“lacking HDAC6 display no gross phenotypes indicative of defective cilia function or cell cycle progression (338) sug-”
Kim, H., Lee, J.-H., Bae, S., Ryoo, H., Kim, H., Ha, H., & Lee, Z. H. (2011) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.426 · Cited by 54
“HDAC6 deficiency led to a small increase in trabecular BMD.((26))”
BackgroundMa, J., Huo, X., Jarpe, M. B., Kavelaars, A., & Heijnen, C. J. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0604-3 · Cited by 73
Lysine deacetylases and mitochondrial dynamics in neurodegeneration
Guedes-Dias, P., & Oliveira, J. M. A. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.04.005 · Cited by 63
“Such allusion, however, contrasts with the original publication in HDAC6-deficient mice, where the respective authors state that no significant increase in tubulin acetylation was found because, in the brain, tubulin is “already highly acetylated” in wild-type animals, and therefore, HDAC6 inactivation has no visible…”
BackgroundResultHdac-Mediated Control of Endochondral and Intramembranous Ossification
Westendorf, J. J., Bradley, E. W., & McGee‐Lawrence, M. E. (2011) · Critical Reviews in Eukaryotic Gene Expression · doi:10.1615/critreveukargeneexpr.v21.i2.10 · Cited by 61
Salmi, M., Bruneau, N., Cillario, J., Lozovaya, N., Massacrier, A., Buhler, E., Cloarec, R., Tsintsadze, T. S., Françoise Watrin, A., Tsintsadze, V., et al. (2013) · Brain · doi:10.1093/brain/awt161 · Cited by 59
“This is also in line with the viability and normal development of Hdac6 knock-out mice (Zhang et al., 2008).”
ResultScott, G. K., Marx, C., Berger, C. E., Saunders, L. R., Verdin, E. M., Schäfer, S., Jung, M., & Benz, C. C. (2008) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-07-2110 · Cited by 58
“significantly more impaired by loss of HDAC6 catalytic function than by the total absence of HDAC6 protein (12).”
BackgroundInfluentialTubulin Post-Translational Modifications: The Elusive Roles of Acetylation
Carmona, B., Marinho, H. S., Matos, C. L., Nolasco, S., & Soares, H. (2023) · Biology · doi:10.3390/biology12040561 · Cited by 64
“Additionally, if tubulin acetylation severely affected axon trafficking, it would be expected that organisms with altered tubulin acetylation levels would have severe neurological defects, but that is not what was found in several studies, as explained before [166,205,288].”
BackgroundResultInfluentialInhibition of N-terminal ATPase on HSP90 attenuates colitis through enhanced Treg function
Collins, C., Aherne, C. M., Yeckes, A., Pound, K. M., Eltzschig, H., Jedlicka, P., & de Zoeten, E. (2013) · Mucosal Immunology · doi:10.1038/mi.2012.134 · Cited by 56
“Furthermore, this is consistent with studies demonstrating enhanced Treg function in HDAC6 / mice,(4) coinciding with increased HSP90 acetylation correlated with impaired HSP90 function.(37) Based on our hypothesis that HSP90 inhibition with 17-AAG was driving IL-10 expression in a HSF1-dependent manner, we assessed t…”
ResultSkov, V., Larsen, T. S., Thomassen, M., Riley, C. H., Jensen, M. K., Bjerrum, O. W., Kruse, T. A., & Hasselbalch, H. C. (2011) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2011.597905 · Cited by 57
Onishi, T., Maeda, R., Terada, M., Sato, S., Fujii, T., Ito, M., Hashikami, K., Kawamoto, T., & Tanaka, M. (2021) · Scientific Reports · doi:10.1038/s41598-021-94923-w · Cited by 61
Choi, E. W., Song, J. W., Ha, N., Choi, Y. I., & Kim, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-35602-1 · Cited by 65
Ehnert, S., Sreekumar, V., Aspera-Werz, R. H., Sajadian, S. O., Wintermeyer, E., Sandmann, G. H., Bahrs, C., Hengstler, J. G., Godoy, P., & Nussler, A. K. (2017) · Journal of Molecular Medicine · doi:10.1007/s00109-017-1526-4 · Cited by 60
“In a mouse model, HDAC6-deficiency results in the expected hyperacetylation of α-tubulin and significantly higher bone mineral density [51].”
BackgroundPrimary cilium: an elaborate structure that blocks cell division?
Ke, Y., & Yang, W. (2014) · Gene · doi:10.1016/j.gene.2014.06.050 · Cited by 64
“Furthermore, HDAC6 is not the sole terminal effector of ciliary disassembly since the HDAC6 knockout is not lethal (Zhang et al., 2008).”
BackgroundSpecific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice.
Regna, N. L., Vieson, M. D., Luo, X. M., Chafin, C. B., Puthiyaveetil, A. G., Hammond, S., Caudell, D., Jarpe, M., & Reilly, C. (2016) · Clinical Immunology · doi:10.1016/j.clim.2015.11.007 · Cited by 55
Revisiting Histone Deacetylases in Human Tumorigenesis: The Paradigm of Urothelial Bladder Cancer
Giannopoulou, A. F., Velentzas, A. D., Konstantakou, E. G., Avgeris, M., Katarachia, S. A., Papandreou, N. C., Kalavros, N., Mpakou, V., Iconomidou, V. A., Anastasiadou, E., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061291 · Cited by 62
Mobley, R. J., Raghu, D., Duke, L. D., Abell-Hart, K., Zawistowski, J. S., Lutz, K., Gomez, S. M., Roy, S., Homayouni, R., Johnson, G. L., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.030 · Cited by 62
“In contrast, HDAC6 knockout mice develop normally (Zhang et al., 2008).”
BackgroundNagai, T., Ikeda, M., Chiba, S., Kanno, S., & Mizuno, K. (2013) · Journal of Cell Science · doi:10.1242/jcs.127209 · Cited by 59
“Although neither a defect nor an excess of tubulin acetylation causes a severe phenotype in Tetrahymena, nematodes and mice (Fukushige et al., 1999; Gaertig et al., 1995; Zhang et al., 2008), tubulin acetylation does modulate the ability of MTs to bind to MAPs and motor proteins, and may regulate MT stability and func…”
BackgroundDriscoll, J. J., & Chowdhury, R. D. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.06.016 · Cited by 50
Histone deacetylase 6 gates the synaptic action of acute stress in prefrontal cortex
Lee, J. B., Wei, J., Liu, W., Cheng, J., Feng, J., & Yan, Z. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2011.224907 · Cited by 52
Zhou, X., Fan, L. X., Li, K., Ramchandran, R., Calvet, J. P., & Li, X. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt556 · Cited by 55
“only subtle phenotypes affecting the immune response and bone density rather than gross abnormalities and embryonic lethality (22), which would be expected if a lack of this protein caused hyperstable microtubules or persistent cilia.”
BackgroundHistone deacetylases as targets for the treatment of human neurodegenerative diseases
D’Mello, S. R. (2009) · Drug News & Perspectives · doi:10.1358/dnp.2009.22.9.1437959 · Cited by 53
Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma
Auzmendi-Iriarte, J., Saenz‐Antoñanzas, A., Mikelez-Alonso, I., Carrasco‐García, E., Tellaetxe-Abete, M., Lawrie, C. H., Samprón, N., Cortajarena, A. L., & Matheu, A. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2586-x · Cited by 60
Nakakura, T., Asano-Hoshino, A., Suzuki, T., Arisawa, K., Tanaka, H., Sekino, Y., Kiuchi, Y., Kawai, K., & Hagiwara, H. (2014) · Medical Molecular Morphology · doi:10.1007/s00795-014-0076-x · Cited by 53
“Histone deacetylase 6 (HDAC6) is recently identified as a cytoplasmic enzyme for the deacetylation of lysine residues in a-tubulin [52, 53].”
BackgroundThe growing landscape of tubulin acetylation: lysine 40 and many more
Sadoul, K., & Khochbin, S. (2016) · Biochemical Journal · doi:10.1042/bcj20160172 · Cited by 53
Self-citationMAPping out distribution routes for kinesin couriers
Atherton, J., Houdusse, A., & Moores, C. A. (2013) · Biology of the Cell · doi:10.1111/boc.201300012 · Cited by 54
“Finally, HDAC6 knockout mice develop normally despite widespread tubulin hyperacetylation (Zhang et al., 2008).”
BackgroundDevelopment of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia
Toutah, K., Nawar, N., Timonen, S., Sorger, H., Raouf, Y. S., Bukhari, S., von Jan, J., Ianevski, A., Gawel, J. M., Olaoye, O. O., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00420 · Cited by 51
Yin, H., Kang, Z., Zhang, Y., Gong, Y., Liu, M., Xue, Y., He, W., Wang, Y., Zhang, S., Xu, Q., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab313 · Cited by 54
Self-citationHa, N., Choi, Y. I., Jung, N., Song, J. Y., Bae, D. K., Kim, M. C., Lee, Y. J., Song, H., Kwak, G., Jeong, S., et al. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15231 · Cited by 55
“In addition, HDAC6 is a safe target for inhibition because HDAC6 knockout mice are viable and fertile with a normal lifespan (Seidel et al., 2015; Zhang et al., 2008).”
BackgroundHDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis.
Gradilone, S., Habringer, S., Masyuk, T., Howard, B. N., Masyuk, A., & LaRusso, N. (2014) · American Journal of Pathology · doi:10.1016/j.ajpath.2013.11.027 · Cited by 49
Hong, J. M., Teitelbaum, S. L., Kim, T., Ross, F. P., Kim, S., & Kim, H. (2010) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.241 · Cited by 48
“Finally, failure to acetylate or deacetylate tubulin enhances bone mass presumably owing to osteoclast dysfunction.((5,33)) We found that Capn6, which is inhibited by GCs, binds to and acetylates osteoclast tubulin, thereby stabilizing the cell’s microtubules.”
BackgroundLoss of HDAC6 alters gut microbiota and worsens obesity
Lieber, A. D., Beier, U. H., Xiao, H., Wilkins, B. J., Jiao, J., Li, X. S., Schugar, R. C., Strauch, C., Wang, Z., Brown, J. M., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201701586r · Cited by 58
New explanations for old observations: marginal band coiling during platelet activation
Sadoul, K. (2015) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12819 · Cited by 47
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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