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HDAC6 is a unique cytoplasmic deacetylase capable of interacting with ubiquitin. Using a combination of biophysical, biochemical and biological approaches, we have characterized the ubiquitin-binding domain of HDAC6, named ZnF-UBP, and investigated its biological functions. These studies show that the three Zn ion-containing HDAC6 ZnF-UBP domain presents the highest known affinity for ubiquitin monomers and mediates the ability of HDAC6 to negatively control the cellular polyubiquitin chain turnover. We further show that HDAC6-interacting chaperone, p97/VCP, dissociates the HDAC6-ubiquitin complexes and counteracts the ability of HDAC6 to promote the accumulation of polyubiquitinated proteins. We propose that a finely tuned balance of HDAC6 and p97/VCP concentrations determines the fate of ubiquitinated misfolded proteins: p97/VCP would promote protein degradation and ubiquitin turnover, whereas HDAC6 would favour the accumulation of ubiquitinated protein aggregates and inclusion body formation.

Original publication

DOI

10.1038/sj.emboj.7601210

Type

Journal article

Journal

EMBO J

Publication Date

26/07/2006

Volume

25

Pages

3357 - 3366

Keywords

3T3 Cells, Adenosine Triphosphatases, Amino Acid Sequence, Animals, COS Cells, Cell Cycle Proteins, Cercopithecus aethiops, HeLa Cells, Histone Deacetylase 6, Histone Deacetylases, Humans, Mice, Mice, Knockout, Molecular Sequence Data, Polyubiquitin, Protein Folding, Valosin Containing Protein