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Molecular and Cellular Biology, December 2007, p. 8637-8647, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00393-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Histone Deacetylase 6 Regulates Growth Factor-Induced Actin Remodeling and Endocytosis{triangledown}

Ya-sheng Gao,1 Charlotte C. Hubbert,1,{dagger} Jianrong Lu,2 Yi-Shan Lee,1 Joo-Yong Lee,1 and Tso-Pang Yao1*

Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710,1 Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 326112

Received 5 March 2007/ Returned for modification 15 April 2007/ Accepted 28 September 2007

Histone deacetylase 6 (HDAC6) is a cytoplasmic deacetylase that uniquely catalyzes {alpha}-tubulin deacetylation and promotes cell motility. However, the mechanism underlying HDAC6-dependent cell migration and the role for microtubule acetylation in motility are not known. Here we show that HDAC6-induced global microtubule deacetylation was not sufficient to stimulate cell migration. Unexpectedly, in response to growth factor stimulation, HDAC6 underwent rapid translocation to actin-enriched membrane ruffles and subsequently became associated with macropinosomes, the vesicles for fluid-phase endocytosis. Supporting the importance of these associations, membrane ruffle formation, macropinocytosis, and cell migration were all impaired in HDAC6-deficient cells. Conversely, elevated HDAC6 levels promoted membrane ruffle formation with a concomitant increase in macropinocytosis and motility. In search for an HDAC6 target, we found that heat shock protein 90 (Hsp90), another prominent substrate of HDAC6, was also recruited to membrane ruffles and macropinosomes. Significantly, inhibition of Hsp90 activity suppressed membrane ruffling and cell migration, while expression of an acetylation-resistant Hsp90 mutant promoted ruffle formation. Our results uncover a surprising role for HDAC6 in actin remodeling-dependent processes and identify the actin cytoskeleton as an important target of HDAC6-regulated protein deacetylation.

* Corresponding author. Mailing address: Duke University, Department of Pharmacology and Cancer Biology, C325 LSRC, Box 3813, Research Drive, Durham, NC 27710. Phone: (919) 613-8654. Fax: (919) 668-3954. E-mail: yao00001{at}mc.duke.edu

{triangledown} Published ahead of print on 15 October 2007.

{dagger} Present address: Howard Hughes Medical Institute, Department of Pharmacology, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98195.

Molecular and Cellular Biology, December 2007, p. 8637-8647, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00393-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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