title: Lymphocyte chemotaxis is regulated by histone deacetylase 6, independently of its deacetylase activity.
abstract: 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.
authors.affiliation: Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain.
authors.forename: J Román
authors.initials: JR
authors.lastname: Cabrero
authors.forename: Juan M
authors.initials: JM
authors.lastname: Serrador
authors.forename: Olga
authors.initials: O
authors.lastname: Barreiro
authors.forename: María
authors.initials: M
authors.lastname: Mittelbrunn
authors.forename: Salvador
authors.initials: S
authors.lastname: Naranjo-Suárez
authors.forename: Noa
authors.initials: N
authors.lastname: Martín-Cófreces
authors.forename: Miguel
authors.initials: M
authors.lastname: Vicente-Manzanares
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Jesús
authors.initials: J
authors.lastname: Avila
authors.forename: Agustín
authors.initials: A
authors.lastname: Valenzuela-Fernández
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
mesh_terms: D000107:Acetylation; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002464:Cell Migration Inhibition; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D015870:Gene Expression; D020868:Gene Silencing; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D050505:Mutant Proteins / Q000378:metabolism; D021381:Protein Transport; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D014404:Tubulin / Q000378:metabolism
chemical_list: D000813:Anilides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050505:Mutant Proteins; D014404:Tubulin; C474316:tubacin; C012589:trichostatin A; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases