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22 (5): 1168-1179

Copyright © 2003 by the European Molecular Biology Organization.

HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo

Yu Zhang, Na Li, Cécile Caron1, Gabriele Matthias, Daniel Hess, Saadi Khochbin1, and Patrick Matthias2

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland and 1 INSERM U309, Institut Albert Bonniot, Faculté de Médecine, Domaine de la Merci, 38706 La Tronche Cedex, France 2 Corresponding author e-mail: matthias{at}fmi.ch

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 ß-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.

Key Words: Keywords: chromatin/cytoskeleton/deacetylase/HDAC (histone deacetylase)/tubulin

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