HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions
Author:
Tran Andy Dong-Anh1, Marmo Timothy P.1, Salam Ambar A.1, Che Sally1, Finkelstein Erik1, Kabarriti Rafi1, Xenias Harry S.1, Mazitschek Ralph2, Hubbert Charlotte3, Kawaguchi Yoshiharu3, Sheetz Michael P.1, Yao Tso-Pang3, Bulinski J. Chloë14
Affiliation:
1. Department of Biological Sciences, Columbia University, New York, NY 10027, USA 2. Broad Institute and Chemical Biology Program, Harvard University and Massachusetts Institute of Technology, 320 Bent Street, Cambridge, MA 02141, USA 3. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA 4. Department of Pathology and Cell Biology, Colleges of Arts and Sciences and Physicians and Surgeons, Columbia University, New York, NY 10027, USA
Abstract
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 α-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.
Publisher
The Company of Biologists
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