HDAC6 Modulates Cell Motility by Altering the Acetylation Level of Cortactin

Abstract

Histone deacetylase 6 (HDAC6) is a tubulin-specific deacetylase that regulates microtubule-dependent cell movement. In this study, we identify the F-actin-binding protein cortactin as a HDAC6 substrate. We demonstrate that HDAC6 binds cortactin and that overexpression of HDAC6 leads to hypoacetylation of cortactin, whereas inhibition of HDAC6 activity leads to cortactin hyperacetylation. HDAC6 alters the ability of cortactin to bind F-actin by modulating a "charge patch" in its repeat region. Introduction of charge-preserving or charge-neutralizing mutations in this cortactin repeat region correlates with the gain or loss of F-actin binding ability, respectively. Cells expressing a charge-neutralizing cortactin mutant were less motile than control cells or cells expressing a charge-preserving mutant. These findings suggest that, in addition to its role in microtubule-dependent cell motility, HDAC6 influences actin-dependent cell motility by altering the acetylation status of cortactin, which, in turn, changes the F-actin binding activity of cortactin.

Alcohol consumption impairs hepatic protein trafficking: mechanisms and consequences

“…At present, the exact mechanism by which cortactin, actin and dynamin function to promote vesicle release is not yet completely elucidated. However, acetylation of cortactin is known to prevent its association with actin [116]. From these results, we propose that alcohol-induced hyperacetylation leads to decreased interactions between actin and cortactin such that cortactin is no longer recruited to sites of clathrin-vesicle formation, thereby inhibiting dynamin recruitment and subsequent vesicle fission.…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…In 2007, Zhang and collaborators identified an F-actin binding protein, cortactin, as a new target for acetylation. Cortactin acetylation is regulated through different factors (PCAF, p300, HDAC6, and SIRT1), leading to the reduction of cortactin binding to F-actin and cell mobility [189,190]. Recently, Cortactin acetylation was also shown to affect dendritic spine morphogenesis, promoting the dendritic clustering of PSD95 and Shank1, two post-synaptic proteins, in excitatory hippocampal synapses.…”

Depression of mitochondrial metabolism by downregulation of cytoplasmic deacetylase, HDAC6

“…Early studies found that HDAC6-mediated a-tubulin deacetylation destabilizes dynamic microtubules [3] and promotes an increase in cell motility [4,5]. In addition to a-tubulin, several cytoplasmic proteins including Hsp90 [6,7], cortactin [8], b-catenin [9], peroxiredoxins I and II [10], and Ku70 [11] are regulated in a HDAC6-mediated deacetylation-dependent manner. Strong ubiquitin binding activity [12,13] further adds to the multifunctionality of HDAC6, enabling the regulation of many important processes including cell migration, cell stress response to the cytotoxic accumulation of protein aggregates, and immune synapse formation [1,2].…”