Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis.
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.
Gao
Ya-sheng
YS
Duke University, Department of Pharmacology and Cancer Biology, Durham, NC 27710, USA.
Hubbert
Charlotte C
CC
Lu
Jianrong
J
Lee
Yi-Shan
YS
Lee
Joo-Yong
JY
Yao
Tso-Pang
TP
D000107:Acetylation / Q000187:drug effects; D000199:Actins / Q000378:metabolism*; D000818:Animals; D002384:Catalysis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D022081:Cell Surface Extensions / Q000187:drug effects / Q000201:enzymology; D004705:Endocytosis / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000187:drug effects / Q000201:enzymology; D010873:Pinocytosis / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D018841:HSP90 Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D020830:rac1 GTP-Binding Protein