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MBC in Press, published online ahead of print May 31, 2006
Mol. Biol. Cell 10.1091/mbc.E06-01-0008

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Submitted on January 4, 2006
Revised on May 17, 2006
Accepted on May 18, 2006

Lymphocyte Chemotaxis Is Regulated by Histone Deacetylase 6, Independently of Its Deacetylase Activity

J. Román Cabrero,*{dagger} Juan M. Serrador,*{dagger}{ddagger} Olga Barreiro,* María Mittelbrunn,* Salvador Naranjo-Suárez,* Noa Martín-Cófreces,* Miguel Vicente-Manzanares,* Ralph Mazitschek,{sect} James E. Bradner,{sect} Jesús Ávila,|| Agustín Valenzuela-Fernández,* and Francisco Sánchez-Madrid*

*Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain; {ddagger}Centro Nacional de Investigaciones Cardiovasculares (CNIC), Unidad Mixta CNIC-Universitat de Valencia, 46010 Valencia, Spain; {sect}Chemical Biology Program, The Broad Institute of Harvard University and Massachusetts Institute of Technology Cambridge, MA 02141; ||Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain

Monitoring Editor: Martin A. Schwartz

In this work, the role of HDAC6, a type II histone deacetylase with tubulin deacetylase activity, in lymphocyte polarity, motility and transmigration was explored. HDAC6 was localized at dynamic subcellular structures as leading lamellipodia and the uropod in migrating T-cells. However, HDAC6 activity did not appear to be involved in the polarity of migrating lymphocytes. Overexpression of HDAC6 in freshly isolated lymphocytes and T-cell lines increased the lymphocyte migration mediated by chemokines, and their transendothelial migration under shear flow. Accordingly, the knockdown of HDAC6 expression in T-cells diminished their chemotactic capability. Additional experiments with HDAC6 inhibitors (Trichostatin, Tubacin), other structural related molecules (Niltubacin, MAZ-1391) and HDAC6 dead mutants showed that the deacetylase activity of HDAC6 was not involved in the modulatory effect of this molecule on cell migration. Our results indicate that HDAC6 has an important role in the chemotaxis of T lymphocytes, which is independent of its tubulin deacetylase activity.

{dagger}These authors contributed equally to this work.

Address correspondence to: Francisco Sánchez-Madrid (fsanchez.hlpr{at}salud.madrid.org)




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