HDAC6–p97/VCP controlled polyubiquitin chain turnover
Abstract
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.
Acknowledgments
We gratefully acknowledge the association ‘vaincre la mucoviscidose' for supporting CB with PhD fellowship for 4 years. BG was supported by ‘association pour la recherche sur le cancer' for his fourth year of PhD fellowship. SK laboratory was supported by ‘region Rhône Alpes theme prioritaire Cancer' programme and CLARA cancéropôle. We gratefully acknowledge the expert assistance of Sandrine Benitski in tissue culture work. The work in PM laboratory was supported by the Novartis Research Foundation. We thank the Ion Beam Centre at the University of Surrey, Guildord, UK for facilities access and Dr I Gomez-Morilla for beamline assistance there.