Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm

Abstract

The intracellular localization, and thereby the function, of a number of key regulator proteins tagged with a short leucine-rich motif (the nuclear export signal or NES) is controlled by CRM1/exportin1, which is involved in the export of these proteins from the nucleus [1]. A common characteristic of these regulators is their transient action in the nucleus during either a specific phase of the cell cycle or in response to specific signals [1]. Here, we show that a particular member of the class II histone-deacetylases mHDA2/mHDAC6 [2] belongs to this family of cellular regulators that are present predominantly in the cytoplasm, but are also capable of shuttling between the nucleus and the cytoplasm. A very potent NES present at the amino terminus of mHDAC6 was found to play an essential role in this shuttling process. The sub-cellular localization of mHDAC6 appeared to be controlled by specific signals, since the arrest of cell proliferation was found to be associated with the translocation of a fraction of the protein into the nucleus. Data presented here suggest that mHDAC6 might be the first member of a functionally distinct class of deacetylases, responsible for activities not shared by other known histone deacetylases.

Class II histone deacetylases: versatile regulators

“…In the absence of a stimulus, the majority of HDAC6 is localized to the cytoplasm, but cell-cycle arrest is associated with the partial translocation of the protein to the cell nucleus [85]. HDAC10 is also primarily cytoplasmic but shows significant nuclear staining in several cell lines [8][9][10]12].…”

“…HDAC10 is also primarily cytoplasmic but shows significant nuclear staining in several cell lines [8][9][10]12]. The cytoplasmic location of both HDAC6 and HDAC10, unlike that of class IIa HDACs, is insensitive to leptomycin B [8,9,85]. The subcellular localization of HDAC6 is dependent on a strong nuclear export signal (NES1) in the N-terminus of the protein [85].…”

“…The cytoplasmic location of both HDAC6 and HDAC10, unlike that of class IIa HDACs, is insensitive to leptomycin B [8,9,85]. The subcellular localization of HDAC6 is dependent on a strong nuclear export signal (NES1) in the N-terminus of the protein [85]. Several putative export sequences were identified in HDAC10 [8,12], but it is not known whether they function as true export signals.…”

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

“…Early investigations considering mouse HDAC6 showed that the protein is actively retained in the cytoplasm and could, only under specific circumstances, be partially found in the nucleus (Verdel et al, 2000). Indeed, a strong nuclear export signal (NES) located N terminus to the first catalytic domain prevents the accumulation of the protein in the nucleus (Figure 1).…”

“…The identification of HDAC6 as the first HDAC actively maintained in the cytoplasm (Verdel et al, 2000) opened the way for the identification of its substrates and cellular functions controlled by its catalytic activity in this compartment. Further analyses of HDAC6 functions revealed the involvement of the protein in cellular processes dependent and independent of its catalytic activity.…”