HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions.
Genetic or pharmacological alteration of the activity of the histone deacetylase 6 (HDAC6) induces a parallel alteration in cell migration. Using tubacin to block deacetylation of alpha-tubulin, and not other HDAC6 substrates, yielded a motility reduction equivalent to agents that block all NAD-independent HDACs. Accordingly, we investigated how the failure to deacetylate tubulin contributes to decreased motility in HDAC6-inhibited cells. Testing the hypothesis that motility is reduced because cellular adhesion is altered, we found that inhibiting HDAC6 activity towards tubulin rapidly increased total adhesion area. Next, we investigated the mechanism of the adhesion area increase. Formation of adhesions proceeded normally and cell spreading was more rapid in the absence of active HDAC6; however, photobleaching assays and adhesion breakdown showed that adhesion turnover was slower. To test the role of hyperacetylated tubulin in altering adhesion turnover, we measured microtubule dynamics in HDAC6-inhibited cells because dynamic microtubules are required to target adhesions for turnover. HDAC6 inhibition yielded a decrease in microtubule dynamics that was sufficient to decrease focal adhesion turnover. Thus, our results suggest a scenario in which the decreased dynamics of hyperacetylated microtubules in HDAC6-inhibited cells compromises their capacity to mediate the focal adhesion dynamics required for rapid cell migration.
Tran
Andy Dong-Anh
AD
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Marmo
Timothy P
TP
Salam
Ambar A
AA
Che
Sally
S
Finkelstein
Erik
E
Kabarriti
Rafi
R
Xenias
Harry S
HS
Mazitschek
Ralph
R
Hubbert
Charlotte
C
Kawaguchi
Yoshiharu
Y
Sheetz
Michael P
MP
Yao
Tso-Pang
TP
Bulinski
J Chloë
JC
D000107:Acetylation; D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion; D002465:Cell Movement; D002522:Chlorocebus aethiops; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D014404:Tubulin / Q000378:metabolism*
D014404:Tubulin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases