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

Abstract

Histone deacetylase 6 (HDAC6) is a unique enzyme with specific structural and functional features. It is actively or stably maintained in the cytoplasm and is the only member, within the histone deacetylase family, that harbors a full duplication of its deacetylase homology region followed by a specific ubiquitin-binding domain at the C-terminus end. Accordingly, this deacetylase functions at the heart of a cellular regulatory mechanism capable of coordinating various cellular functions largely relying on the microtubule network. Moreover, HDAC6 action as a regulator of the HSP90 chaperone activity adds to the multifunctionality of the protein, and allows us to propose a critical role for HDAC6 in mediating and coordinating various cellular events in response to different stressful stimuli.

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

“…In contrast, HDAC6 resides exclusively in the cytoplasm presumably due to its tetradecapeptide repeat domain and its association with cytoskeletal components (Bertos et al, 2004;Valenzuela-Fernández et al, 2008). Consistent with the localization pattern of HDAC6, it mainly participates in cytoskeleton-related activities, independently of histone modification (Boyault et al, 2007;Valenzuela-Fernández et al, 2008). In this scenario, it is likely that the action of HDAC6 in angiogenesis is independent of gene transcription but instead involves cytoskeleton-associated events.…”

“…A number of HDAC inhibitors are in clinical development as anticancer agents (Xu et al, 2007), and one of them, suberoylanilide hydroxamic acid, has recently been approved for the treatment of advanced cutaneous T cell lymphoma (Marks, 2007). While most of the HDACs are localized in the nucleus, HDAC6 is a cytoplasmic protein associated with the cytoskeleton and involved in cytoskeleton-related activities (Boyault et al, 2007;Valenzuela-Fernández et al, 2008). There is a growing body of evidence showing that HDAC6 functions at the intersection of the cytoskeleton and cell signaling to regulate cell motility, cell adhesion, and cell-cell interactions (Boyault et al, 2007;Valenzuela-Fernández et al, 2008).…”

“…While most of the HDACs are localized in the nucleus, HDAC6 is a cytoplasmic protein associated with the cytoskeleton and involved in cytoskeleton-related activities (Boyault et al, 2007;Valenzuela-Fernández et al, 2008). There is a growing body of evidence showing that HDAC6 functions at the intersection of the cytoskeleton and cell signaling to regulate cell motility, cell adhesion, and cell-cell interactions (Boyault et al, 2007;Valenzuela-Fernández et al, 2008). These findings suggest that this deacetylase might have a role in angiogenesis, which is critically dependent on the aforementioned cellular activities (Lamalice et al, 2007).…”

Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis

“…The double catalytic domain, a ubiquitin-binding domain, and a nuclear export-signal domain are functionally conserved in mouse and human HDAC6, mediating the same deacetylase, [27] . It has been documented that the ubiquitinbinding domain plays an important role in HDAC6-mediated autophagosome maturation and autophagosome-lysosome fusion [14,15] .…”

“…Histone deacetylase 6 (HDAC6) is a unique class II deacetylase containing a ubiquitin-binding domain; it copes with excessive levels of misfolded proteins by recruiting them to dynein motors for transport to aggresomes [13,14] .…”