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HDAC6 is a microtubule-associated deacetylase

Abstract

Reversible acetylation of α-tubulin has been implicated in regulating microtubule stability and function1. The distribution of acetylated α-tubulin is tightly controlled and stereotypic. Acetylated α-tubulin is most abundant in stable microtubules but is absent from dynamic cellular structures such as neuronal growth cones and the leading edges of fibroblasts1,2. However, the enzymes responsible for regulating tubulin acetylation and deacetylation are not known. Here we report that a member of the histone deacetylase family, 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 containing p150glued (ref. 3). In vivo, the overexpression of HDAC6 leads to a global deacetylation of α-tubulin, whereas a decrease in HDAC6 increases α-tubulin acetylation. In vitro, purified HDAC6 potently deacetylates α-tubulin in assembled microtubules. Furthermore, overexpression of HDAC6 promotes chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility. Our results show that HDAC6 is the tubulin deacetylase, and provide evidence that reversible acetylation regulates important biological processes beyond histone metabolism and gene transcription.

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Figure 1: Co-localization of HDAC6 with p150glued and the microtubule network.
Figure 2: HDAC6 is a tubulin deacetylase in vivo.
Figure 3: Recombinant HDAC6 exhibits tubulin deacetylase activity towards assembled microtubules in vitro.
Figure 4: Overexpression of HDAC6 increases the chemotactic motility of NIH-3T3 cells.

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Acknowledgements

We thank A. R. Means, A. M. Pendergast and A. M. J. Van Dongen, as well as the members of the Yao laboratory, for their insightful discussions and critical reading of the manuscript; A. M. Pendergast for pointing out the similarity between HDAC6 and p150glued; and J. Gross and H. Solari for technical assistance with the confocal microscopy. X.F.W. was supported by an NIH grant, as was A.N. (to P. J. Casey). This work is supported by funding from the Damon Runyon–Walter Winchell Cancer Foundation and the Department of Defense to T.-P.Y.

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Correspondence to Tso-Pang Yao.

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Hubbert, C., Guardiola, A., Shao, R. et al. HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458 (2002). https://doi.org/10.1038/417455a

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