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.

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

“…HDAC6 overexpression promoted chemotactic movement of fibroblasts and lymphocytes, suggesting that HDAC6-mediated tubulin deacetylation regulates microtubule-dependent cell motility. 55,56 Nevertheless, there is contradictory data on the importance of HDAC6 in regulation of cellular motility (reviewed in ref. 57).…”

“…57). It has therefore been proposed that HDAC6 expression per se but not its tubulin deacetylase activity is important for its effect on cell migration 56 and that these effects may be mediated by downstream factors like HSP90. 58 As high micromolar drug concentrations are impractical for clinical applications, we sought to find suitable combination regimens that would allow a dose reduction through synergistic effects.…”

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

“…Indeed, Cabrero et al (2006) have recently found that the cellular levels of HDAC6 and not its catalytic activity are critical for lymphocyte chemotaxis.…”

Depression of mitochondrial metabolism by downregulation of cytoplasmic deacetylase, HDAC6

“…Indeed, loss of HDAC6 causes a reduction in cell motility both in NIH/3T3 fibroblasts [4,5] and lymphocytes [24]. HDAC6 may thus be a cellular homeostasis surveillance factor.…”