Lymphocyte chemotaxis is regulated by histone deacetylase 6, independently of its deacetylase activity.
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.
Cabrero
J Román
JR
Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain.
Serrador
Juan M
JM
Barreiro
Olga
O
Mittelbrunn
María
M
Naranjo-Suárez
Salvador
S
Martín-Cófreces
Noa
N
Vicente-Manzanares
Miguel
M
Mazitschek
Ralph
R
Bradner
James E
JE
Avila
Jesús
J
Valenzuela-Fernández
Agustín
A
Sánchez-Madrid
Francisco
F
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
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