In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation.
Trichostatin A (TSA) inhibits all histone deacetylases (HDACs) of both class I and II, whereas trapoxin (TPX) cannot inhibit HDAC6, a cytoplasmic member of class II HDACs. We took advantage of this differential sensitivity of HDAC6 to TSA and TPX to identify its substrates. Using this approach, alpha-tubulin was identified as an HDAC6 substrate. HDAC6 deacetylated alpha-tubulin both in vivo and in vitro. Our investigations suggest that HDAC6 controls the stability of a dynamic pool of microtubules. Indeed, we found that highly acetylated microtubules observed after TSA treatment exhibited delayed drug-induced depolymerization and that HDAC6 overexpression prompted their induced depolymerization. Depolymerized tubulin was rapidly deacetylated in vivo, whereas tubulin acetylation occurred only after polymerization. We therefore suggest that acetylation and deacetylation are coupled to the microtubule turnover and that HDAC6 plays a key regulatory role in the stability of the dynamic microtubules.
Matsuyama
Akihisa
A
Chemical Genetics Laboratory, Wako, Saitama 351-0198, Japan.
Shimazu
Tadahiro
T
Sumida
Yuko
Y
Saito
Akiko
A
Yoshimatsu
Yasuhiro
Y
Seigneurin-Berny
Daphné
D
Osada
Hiroyuki
H
Komatsu
Yasuhiko
Y
Nishino
Norikazu
N
Khochbin
Saadi
S
Horinouchi
Sueharu
S
Yoshida
Minoru
M
D000107:Acetylation; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D003703:Demecolcine / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D015151:Immunoblotting; D051379:Mice; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D013997:Time Factors; D014162:Transfection; D014404:Tubulin / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D010455:Peptides; D014404:Tubulin; D000431:Ethanol; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D003703:Demecolcine