title: HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo.
abstract: 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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Cécile
authors.initials: C
authors.lastname: Caron
authors.forename: Gabriele
authors.initials: G
authors.lastname: Matthias
authors.forename: Daniel
authors.initials: D
authors.lastname: Hess
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthias
mesh_terms: D016475:3T3 Cells; D000107:Acetylation; D000818:Animals; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004622:Embryo, Mammalian / Q000033:anatomy & histology; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D017239:Paclitaxel / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D010455:Peptides; D014404:Tubulin; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D017239:Paclitaxel