HDAC6: A key regulator of cytoskeleton, cell migration and cell-cell interactions

Departamento de Medicina Física y Farmacología, Facultad de Medicina and Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, Tenerife, Spain.
Trends in cell biology (Impact Factor: 12.01). 07/2008; 18(6):291-7. DOI: 10.1016/j.tcb.2008.04.003
Source: PubMed


Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that regulates many important biological processes, including cell migration, immune synapse formation, viral infection, and the degradation of misfolded proteins. HDAC6 deacetylates tubulin, Hsp90 and cortactin, and forms complexes with other partner proteins. Although HDAC6 enzymatic activity seems to be required for the regulation of cell morphology, the role of HDAC6 in lymphocyte chemotaxis is independent of its tubulin deacetylase activity. The diverse functions of HDAC6 suggest that it is a potential therapeutic target for the treatment of a range of diseases. This review examines the biological actions of HDAC6, focusing on its deacetylase activity and its potential scaffold functions in the regulation of cell migration and other key biological processes in which the cytoskeleton plays an important role.

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Available from: Agustin Valenzuela-Fernandez, Aug 17, 2014
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    ABSTRACT: Functional assays, such as the "migration inhibition of neural crest cells"(MINC) developmental toxicity test, can identify toxicants without requiring knowledge on their mode of action (MoA). Here, we were interested, whether (i) inhibition of migration by structurally diverse toxicants resulted in a unified signature of transcriptional changes; (ii) whether statistically-identified transcript patterns would inform on compound grouping even though individual genes were little regulated, and (iii) whether analysis of a small group of biologically-relevant transcripts would allow the grouping of compounds according to their MoA. We analysed transcripts of 35 'migration genes' after treatment with sixteen migration-inhibiting toxicants. Clustering, principal component analysis and correlation analyses of the data showed that mechanistically related compounds (e.g. histone deacetylase inhibitors (HDACi)), PCBs) triggered similar transcriptional changes, but groups of structurally diverse toxicants largely differed in their transcriptional effects. Linear discriminant analysis (LDA) confirmed the specific clustering of HDACi across multiple separate experiments. Similarity of the signatures of the HDACi trichostatin A and suberoylanilide hydroxamic acid to the one of valproic acid (VPA), suggested that the latter compound acts as HDACi when impairing neural crest migration. In conclusion, the data suggest that (i) a given functional effect (e.g. inhibition of migration) can be associated with highly diverse signatures of transcript changes; (ii) statistically significant grouping of mechanistically-related compounds can be achieved on the basis of few genes with small regulations. Thus, incorporation of mechanistic markers in functional in vitro tests may support read-across procedures, also for structurally un-related compounds. Copyright © 2015. Published by Elsevier B.V.
    NeuroToxicology 07/2015; 50. DOI:10.1016/j.neuro.2015.07.008 · 3.38 Impact Factor
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    • "HDAC6, as a unique member of the HDAC family with a predominant localization in the cytoplasm, has been implicated in numerous cellular processes such as cell motility, cell-cell interaction, and transcriptional regulation [18], [19]. HDAC6 carries out the above functions primarily through its deacetylation of substrate proteins such as α-tubulin [11]–[13], cortactin [20], and Hsp90 [21]. "
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    ABSTRACT: Microtubule-mediated cellular events such as intracellular transport and the maintenance of cell polarity are highly dependent upon microtubule stability, which is controlled by a repertoire of microtubule-associated proteins (MAPs) in the cell. MAP7 domain-containing protein 3 (Mdp3) has recently been identified as a critical regulator of microtubule stability. However, it remains elusive how Mdp3 carries out this function. In this study, by examination of tubulin partitioning between the polymer and soluble dimer forms, we found that Mdp3 could protect microtubules from cold- or nocodazole-induced depolymerization. Immunoblotting and immunofluorescence microscopy showed that knockdown of Mdp3 expression significantly reduced the level of tubulin acetylation. In vitro tubulin polymerization assays revealed that the amino-terminal region of Mdp3 was necessary for its ability to stabilize microtubules. Immunoprecipitation and pulldown experiments showed that the amino-terminal region mediated the interaction of Mdp3 with histone deacetylase 6 (HDAC6), in addition to its association with tubulin and microtubules. Immunofluorescence microscopy further demonstrated that endogenous Mdp3 and HDAC6 colocalized in the cytoplasm. Moreover, depletion of Mdp3 dramatically increased the activity of HDAC6 toward tubulin deacetylation. These findings suggest that Mdp3 controls microtubule stability through its binding to tubulin and microtubules as well as its regulation of HDAC6 activity.
    PLoS ONE 03/2014; 9(3):e90932. DOI:10.1371/journal.pone.0090932 · 3.23 Impact Factor
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    • "Histone deacetylase-6 (HDAC6), a member of the class II histone deacetylases, is a unique cytosolic enzyme that regulates cell motility (Hubbert et al., 2002; Matsuyama et al., 2002; Zhang et al., 2003; Tran et al., 2007), endocytosis (Gao et al., 2007), vesicle transport (Dompierre et al., 2007), cell migration and degradation of misfolded proteins (Iwata et al., 2005; Valenzuela-Fernandez et al., 2008) and other cellular process by deacetylating α-tubulin, Hsp90 and cortactin (Fukada et al., 2012). HDAC6 has emerged as an attractive target for pharmacological intervention in several CNS diseases. "
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    ABSTRACT: Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). One of the most prominent gene targets of MeCP2 is brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. Dysfunctional BDNF signaling has been demonstrated in several pathophysiological mechanisms of RTT disease progression. To evaluate whether the dynamics of BDNF trafficking is affected by Mecp2 deletion, we analyzed movements of BDNF tagged with yellow fluorescent protein (YFP) in cultured hippocampal neurons by time-lapse fluorescence imaging. We found that both anterograde and retrograde vesicular trafficking of BDNF-YFP are significantly impaired in Mecp2 knockout hippocampal neurons. Selective inhibitors of histone deacetylase 6 (HDAC6) show neuroprotective effects in neurodegenerative diseases and stimulate microtubule-dependent vesicular trafficking of BDNF-containing dense core vesicles. Here, we show that the selective HDAC6 inhibitor Tubastatin-A increased the velocity of BDNF-YFP vesicles in Mecp2 knockout neurons in both directions by increasing α-tubulin acetylation. Tubastatin-A also restored activity-dependent BDNF release from Mecp2 knockout neurons to levels comparable to those shown by wildtype neurons. These findings demonstrate that a selective HDAC6 inhibitor is a potential pharmacological strategy to reverse cellular and synaptic impairments in RTT resulting from impaired BDNF signaling.
    Frontiers in Cellular Neuroscience 03/2014; 8:68. DOI:10.3389/fncel.2014.00068 · 4.29 Impact Factor
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