Alternative titles; symbols
HGNC Approved Gene Symbol: HDAC6
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:48,801,398-48,824,982 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | ?Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia | 300863 | X-linked dominant | 3 |
Histone acetylation (see HAT1; 603053) and deacetylation (see HDAC1; 601241) alternately exposes and occludes DNA to transcription factors. There are at least 2 classes of HDACs, class I consisting of proteins homologous to yeast Rpd3 (e.g., HDAC1, HDAC2 (605164), and HDAC3 (605166)) and class II consisting of proteins homologous to yeast Hda1 (e.g., HDAC4; 605314). HDAC6 belongs to class II.
Nagase et al. (1998) isolated a cDNA encoding HDAC6, which they called KIAA0901, from a brain cDNA library. RT-PCR analysis detected HDAC6 expression in all tissues tested, with highest expression in brain and lowest expression in heart, spleen, and pancreas.
By searching an EST database for sequences similar to yeast Hda1, followed by screening a cDNA library and PCR, Grozinger et al. (1999) identified cDNAs encoding the class II HDACs HDAC4, HDAC5 (605315), and HDAC6. Sequence analysis predicted that the 1,216-amino acid HDAC6 protein consists of an apparent internal dimer containing 2 highly homologous catalytic domains, the first beginning at residue 215 and the second at residue 610. Northern blot analysis detected expression of a 5.0-kb HDAC6 transcript that was highest in heart, liver, kidney, and pancreas. Functional analysis confirmed that HDAC6 possesses deacetylation activity against all 4 core histones and that the 2 catalytic domains function independently. Western blot analysis showed that HDAC6 is expressed as a 131-kD protein that does not coimmunoprecipitate with other HDACs or transcription factors. Grozinger et al. (1999) speculated that HDAC6 may not interact with histones in vivo but may deacetylate other substrates.
Bertos et al. (2004) determined that the human HDAC6 protein contains 8 consecutive serine- and glutamic acid-containing tetradecapeptide (SE14) repeats between the second deacetylase domain and the C-terminal ubiquitin-binding zinc finger. The SE14 domain is not present in orthologs from C. elegans, Drosophila, and mouse. HDAC6 also contains 2 nuclear export signals and a nuclear localization signal.
By in situ hybridization, Mahlknecht et al. (2001) mapped the HDAC6 gene to chromosome Xp11.23.
Hubbert et al. (2002) demonstrated that HDAC6 functions as a tubulin deacetylase. HDAC6 is localized exclusively in the cytoplasm, where it associates with microtubules and localizes with the microtubule motor complex (see 601143). In vivo the overexpression of HDAC6 led to a global deacetylation of alpha-tubulin (see 602529), whereas a decrease in HDAC6 increased alpha-tubulin acetylation. In vitro, purified HDAC6 potently deacetylated alpha-tubulin in assembled microtubules. Furthermore, overexpression of HDAC6 promoted chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility. Hubbert et al. (2002) concluded that HDAC6 is the tubulin deacetylase, and provided evidence that reversible acetylation regulates important biologic processes beyond histone metabolism and gene transcription.
Aggregates of misfolded proteins are transported and removed from the cytoplasm by dynein motors via the microtubule network to an organelle termed the aggresome, where they are processed. Kawaguchi et al. (2003) identified HDAC6 as a component of the aggresome in human cells. HDAC6 could bind both polyubiquitinated misfolded proteins and dynein motors, thereby recruiting misfolded protein cargo to dynein motors for transport to aggresomes. Cells deficient in HDAC6 failed to clear misfolded protein aggregates from the cytoplasm, could not form aggresomes properly, and were hypersensitive to accumulation of misfolded proteins.
Bertos et al. (2004) determined that the SE14 domain of HDAC6 was dispensable for the deacetylase and ubiquitin-binding activities of HDAC6, but it conferred acetyl-microtubule targeting. They further found that HDAC6 maintained a cytoplasmic distribution in the presence of leptomycin B, an inhibitor of nuclear export signals, and that the SE14 domain conferred leptomycin B resistance. The SE14 domain formed a unique structure that caused monomeric HDAC6 to migrate at a molecular mass of about 500 kD by gel filtration, rather than the predicted mass of about 150 kD. Bertos et al. (2004) concluded that the cytoplasmic distribution of HDAC6 is differentially regulated in mice and humans, and that the SE14 domain serves to stably retain human HDAC6 in the cytoplasm.
Kovacs et al. (2005) found that inactivation of HDAC6 in human embryonic kidney cells led to HSP90 (see 140571) hyperacetylation, dissociation of HSP90 from an essential cochaperone, p23 (607061), and loss of chaperone activity. In HDAC6-deficient cells, HSP90-dependent maturation of the glucocorticoid receptor (GCCR; 138040) was compromised, resulting in a receptor defective in ligand binding, nuclear translocation, and transcriptional activation. Kovacs et al. (2005) concluded that HSP90 is a target of HDAC6 and that reversible acetylation is a mechanism that regulates HSP90 chaperone complex activity.
Pandey et al. (2007) demonstrated in Drosophila that autophagy acts as a compensatory degradation system when the ubiquitin proteasome system (UPS) is impaired, and that HDAC6, a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. The authors found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. Pandey et al. (2007) concluded that impairment of autophagy (i.e., associated with aging or genetic variation) might predispose to neurodegeneration. Moreover, their findings suggested that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.
Pugacheva et al. (2007) found that AURKA (603072) and its activator HEF1 (NEDD9; 602265) localized to the basal body and the second centriole in quiescent ciliated human retinal pigment epithelial cells. Association of AURKA with HEF1 in response to extracellular cues was required for ciliary disassembly. Activation of AURKA was independently sufficient to induce rapid ciliary resorption, and AURKA acted in this process through phosphorylation of HDAC6, leading to HDAC6-dependent tubulin deacetylation and destabilization of the ciliary axoneme. Small molecule inhibitors of AURKA and HDAC6 reduced regulated disassembly of cilia.
An immediate response to cell stress is reversible blockade of mRNA translation. Stalled mRNAs are sequestered into cytoplasmic stress granules (SGs), which are complex assemblies of initiation factors and proteins involved in translational control and RNA remodeling or degradation, as well as 40S ribosome subunits and polyadenylated mRNAs whose translation has been arrested. Kwon et al. (2007) showed that the SG protein G3BP (608431) interacted with HDAC6 in vivo and in vitro and that HDAC6 was recruited to SGs. Inhibition of HDAC led to impaired SG assembly, and Hdac6-deficient mouse embryo fibroblasts failed to form SGs, although they exhibited normal phosphorylation of Eif2a (609234) in response to stress. Inactivating mutations in the catalytic domains or the C-terminal zinc finger domain of HDAC6 impaired SG assembly. Kwon et al. (2007) also found that HDAC6 was required for cells to recover from oxidative stress. They proposed that HDAC6 is a central component of the stress response that regulates SG formation and potentially contributes to control of RNA metabolism and translation.
Tsai et al. (2012) showed that human kalirin (KALRN; 604605) isoform-7 promoted recruitment of perinuclear synphilin-1 (SNCAIP; 603779) inclusions into aggresomes in an HDAC6-dependent manner and increased the susceptibility of synphilin-1 inclusions to degradation. Kalirin-7 and synphilin-1 interacted with each other, and both also interacted with HDAC6. All 3 proteins acted as a common complex and increased transportation of synphilin-1 into aggresomes through kalirin-mediated deacetylation of HDAC6.
During cell entry, capsids of incoming influenza A viruses must be uncoated before viral nucleoproteins can enter the nucleus for replication. Banerjee et al. (2014) found that for capsid disassembly, influenza A virus takes advantage of the host cell's aggresome formation and disassembly machinery. The capsids mimicked misfolded protein aggregates by carrying unanchored ubiquitin chains that activated an HDAC6-dependent pathway. The ubiquitin-binding domain was essential for recruitment of HDAC6 to viral fusion sites and for efficient uncoating and infection. The additional requirement of other components of the aggresome processing machinery, including dynein (see 600112), dynactin (see 601143), and myosin II (MYH10; 160776), suggested that physical forces generated by microtubule- and actin-associated motors are essential for influenza A virus entry.
Magupalli et al. (2020) showed that NLRP3 (606416)- and pyrin (MEFV; 608107)-mediated inflammasome assembly, caspase (see 147678) activation, and IL1-beta (IL1B; 147720) conversion occurred at the microtubule-organizing center (MTOC) in mouse and human cells. HDAC6 was required for microtubule transport and assembly of these inflammasomes both in vitro and in mice. The authors noted that because HDAC6 can transport ubiquitinated pathologic aggregates to the MTOC for aggresome formation and autophagosomal degradation, its role in NLRP3 and pyrin inflammasome activation also provides an inherent mechanism for downregulation of these inflammasomes by autophagy.
By ex vivo analysis, Lin et al. (2022) showed that Hdac6 loss of function led to titin (TTN; 188840) stiffening of mouse myofibrils. Hdac6 catalytic activity was required for regulation of myofibril stiffness, because inhibition of Hdac6 in cultured adult rat ventricular myocytes (ARVMs) increased myofibril stiffness, whereas both Hdac6 overexpression in ARVMs and ex vivo treatment of rat and human myofibrils with recombinant HDAC6 led to decreased myofibril stiffness. The PEVK region of titin was required for Hdac6-mediated modulation of myofibril stiffness. HDAC6 could reverse PKC (see 176960)-mediated titin stiffening in human myofibrils, and mechanistic analysis in mice revealed that Hdac6 functioned as a sarcomeric protein deacetylase in regulation of PKC-mediated stiffening of myofibrils independent of phosphorylation. In support, diastolic dysfunction was exacerbated by Hdac6 loss as a result of elevated passive stiffness of heart in mice.
Chassaing et al. (2005) reported a 4-generation family segregating an apparent X-linked dominant chondrodysplasia (300863) with features including intrauterine growth retardation, hydrocephaly, rhizomelic shortening, facial dysmorphism, and microphthalmia. Using X-linked polymorphic microsatellite markers, Simon et al. (2010) performed linkage analysis in the family described by Chassaing et al. (2005) and mapped the disease locus to a 24-Mb interval on chromosome Xp11.3-q13.1 (lod = 3.30). By exon sequencing, Simon et al. (2010) identified a variant in exon 29 of HDAC6, 281 bp after the translation termination codon (c.*281A>T; 300272.0001) that completely segregated with the disorder. The variant was located in the sequence corresponding to the seed sequence of miR433 (611711). Transduction experiments with an HDAC6 3-prime UTR-bearing transgene showed that the mutation abrogated the posttranscriptional regulation normally exerted by this microRNA.
In the 4-generation family with X-linked dominant chondrodysplasia (300863) described by Chassaing et al. (2005), Simon et al. (2010) detected an A-to-T transversion in exon 29 of the HDAC6 gene, in the 3-prime untranslated region 281 basepairs after the TAA translation termination codon (c.*281A-T). The mutation completely cosegregated with the disorder and was not found in SNP databases or in 100 control individuals. The variant was located in the sequence corresponding to the seed sequence of miR433 (611711). In MG63 osteosarcoma cells, miR433 downregulated both the expression of endogenous HDAC6 and that of an enhanced green fluorescent protein-reporter mRNA bearing the wildtype 3-prime UTR of HDAC6. This effect was totally abrogated when the reporter mRNA bore the mutated HDAC6 3-prime UTR. The HDAC6 protein was overexpressed in thymus from an affected male fetus. Concomitantly, the level of total alpha-tubulin (see 602529), a target of HDAC6, was increased in the affected fetal thymus, whereas the level of acetylated alpha-tubulin was profoundly decreased. Skin biopsies from a female patient with striking body asymmetry expressed a mutated HDAC6 allele in 31% of affected arm-derived fibroblasts, whereas it was not expressed in the contralateral arm. Overexpression of HDAC6 was also observed in affected arm-derived fibroblasts. The authors concluded that the HDAC6 3-prime UTR variant suppressed miR433-mediated posttranscriptional regulation, causing overexpression of HDAC6 and resulting in this form of X-linked chondrodysplasia.
Banerjee, I., Miyake, Y., Nobs, S. P., Schneider, C., Horvath, P., Kopf, M., Matthias, P., Helenius, A., Yamauchi, Y. Influenza A virus uses the aggresome processing machinery for host cell entry. Science 346: 473-477, 2014. [PubMed: 25342804] [Full Text: https://doi.org/10.1126/science.1257037]
Bertos, N. R., Gilquin, B., Chan, G. K. T., Yen, T. J., Khochbin, S., Yang, X.-J. Role of the tetradecapeptide repeat domain of human histone deacetylase 6 in cytoplasmic retention. J. Biol. Chem. 279: 48246-48254, 2004. [PubMed: 15347674] [Full Text: https://doi.org/10.1074/jbc.M408583200]
Chassaing, N., Siani, V., Carles, D., Delezoide, A. L., Alberti, E. M., Battin, J., Chateil, J. F., Gilbert-Dussardier, B., Coupry, I., Arveiler, B., Saura, R., Lacombe, D. X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia . Am. J. Med. Genet. 136A: 307-312, 2005. [PubMed: 16001442] [Full Text: https://doi.org/10.1002/ajmg.a.30570]
Grozinger, C. M., Hassig, C. A., Schreiber, S. L. Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc. Nat. Acad. Sci. 96: 4868-4873, 1999. [PubMed: 10220385] [Full Text: https://doi.org/10.1073/pnas.96.9.4868]
Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., Yoshida, M., Wang, X.-F., Yao, T.-P. HDAC6 is a microtubule-associated deacetylase. Nature 417: 455-458, 2002. [PubMed: 12024216] [Full Text: https://doi.org/10.1038/417455a]
Kawaguchi, Y., Kovacs, J. J., McLaurin, A., Vance, J. M., Ito, A., Yao, T.-P. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115: 727-738, 2003. [PubMed: 14675537] [Full Text: https://doi.org/10.1016/s0092-8674(03)00939-5]
Kovacs, J. J., Murphy, P. J. M., Gaillard, S., Zhao, X., Wu, J.-T., Nicchitta, C. V., Yoshida, M., Toft, D. O., Pratt, W. B., Yao, T.-P. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Molec. Cell 18: 601-607, 2005. [PubMed: 15916966] [Full Text: https://doi.org/10.1016/j.molcel.2005.04.021]
Kwon, S., Zhang, Y., Matthias, P. The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response. Genes Dev. 21: 3381-3394, 2007. [PubMed: 18079183] [Full Text: https://doi.org/10.1101/gad.461107]
Lin, Y. H., Major, J. L., Liebner, T., Hourani, Z., Travers, J. G., Wennersten, S. A., Haefner, K. R., Cavasin, M. A., Wilson, C. E., Jeong, M. Y., Han, Y., Gotthardt, M., Ferguson, S. K., Ambardekar, A. V., Lam, M. P., Choudhary, C., Granzier, H. L., Woulfe, K. C., McKinsey, T. A. HDAC6 modulates myofibril stiffness and diastolic function of the heart. J. Clin. Invest. 132: e148333, 2022. [PubMed: 35575093] [Full Text: https://doi.org/10.1172/JCI148333]
Magupalli, V. G., Negro, R., Tian, Y., Hauenstein, A. V., Di Caprio, G., Skillern, W., Deng, Q., Orning, P., Alam, H. B., Maliga, Z., Sharif, H., Hu, J. J., Evavold, C. L., Kagan, J. C., Schmidt, F. I., Fitzgerald, K. A., Kirchhausen, T., Li, Y., Wu, H. HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation. Science 369: eaas8995, 2020. Note: Electronic Article. [PubMed: 32943500] [Full Text: https://doi.org/10.1126/science.aas8995]
Mahlknecht, U., Schnittger, S., Landgraf, F., Schoch, C., Ottmann, O. G., Hiddemann, W., Hoelzer, D. Assignment of the human histone deacetylase 6 gene (HDAC6) to X chromosome p11.23 by in situ hybridization. Cytogenet. Cell Genet. 93: 135-136, 2001. [PubMed: 11474198] [Full Text: https://doi.org/10.1159/000056967]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 355-364, 1998. [PubMed: 10048485] [Full Text: https://doi.org/10.1093/dnares/5.6.355]
Pandey, U. B., Nie, Z., Batlevi, Y., McCray, B. A., Ritson, G. P., Nedelsky, N. B., Schwartz, S. L., DiProspero, N. A., Knight, M. A., Schuldiner, O., Padmanabhan, R., Hild, M., Berry, D. L., Garza, D., Hubbert, C. C., Yao, T.-P., Baehrecke, E. H., Taylor, J. P. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447: 859-863, 2007. [PubMed: 17568747] [Full Text: https://doi.org/10.1038/nature05853]
Pugacheva, E. N., Jablonski, S. A., Hartman, T. R., Henske, E. P., Golemis, E. A. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129: 1351-1363, 2007. [PubMed: 17604723] [Full Text: https://doi.org/10.1016/j.cell.2007.04.035]
Simon, D., Laloo, B., Barillot, M., Barnetche, T., Blanchard, C., Rooryck, C., Marche, M., Burgelin, I., Coupry, I., Chassaing, N., Gilbert-Dussardier, B., Lacombe, D., Grosset, C., Arveiler, B. A mutation in the 3-prime-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia. Hum. Molec. Genet. 19: 2015-2027, 2010. Note: Erratum: Hum. Molec. Genet. 19: 3489-3490, 2010. [PubMed: 20181727] [Full Text: https://doi.org/10.1093/hmg/ddq083]
Tsai, Y.-C., Riess, O., Soehn, A. S.,, Nguyen, H. P. The guanine nucleotide exchange factor kalirin-7 is a novel synphilin-1 interacting protein and modifies synphilin-1 aggregate transport and formation. PLoS One 7: e51999, 2012. Note: Electronic Article. [PubMed: 23284848] [Full Text: https://doi.org/10.1371/journal.pone.0051999]