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.

Histone deacetylase inhibitors: molecular mechanisms of action

“…HDAC6 can bind p150, a component of dynein motor complex, and act as a bridge between the dynein motors and the ubiquitination process, directing the polyubiquitinated proteins to aggresome. HDAC6 has a high affinity for ubiquitin molecule (due to the presence of the ZnF-UBP or BUZ domain) and is involved in the transport of poly-ubiquitinated proteins (Boyault et al, 2006). HDAC6 deacetylase activity is important for transport of misfolded poly-ubiquitinated proteins to the aggresome, and loss of HDAC6 function makes cells more sensitive to misfolded protein stress induced by protease inhibitor and, as a consequence, cell death (Kawaguchi et al, 2003).…”

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

“…This domain has the particularity to specifically bind mono- (Seigneurin-Berny et al, 2001;Boyault et al, 2006) and poly-ubiquitin chains (Hook et al, 2002;Boyault et al, 2006). More detailed studies allowed for the modeling of the structure of this domain in HDAC6 and to predict its organization in three zinc fingers.…”

“…More detailed studies allowed for the modeling of the structure of this domain in HDAC6 and to predict its organization in three zinc fingers. This particular organization of HDAC6 ZnF-UBP domain allows its binding to monomeric ubiquitin with a measured K d of 60 nM, which is the highest known affinity for ubiquitin binding among all known ubiquitin-interacting proteins (Boyault et al, 2006).…”

“…Although this mechanism has not yet been evidenced in higher eukaryotes, the investigation of the ubiquitindependent functions of HDAC6 has also recently revealed its involvement in the determination of the fate of ubiquitinated proteins. High-affinity binding of HDAC6 to ubiquitin was shown to hinder the recognition of cellular ubiquitinated proteins by other ubiquitin-binding factors and to subsequently delay their processing by the proteasome or USPs (Boyault et al, 2006). The HDAC6 partner p97/VCP is a chaperone involved in the control of a variety of cellular functions, many of them relying on its 'segregase' activity disassembling various complexes, including those containing ubiquitinated proteins (Wang et al, 2003;Romisch, 2005).…”

“…Further analyses of HDAC6 functions revealed the involvement of the protein in cellular processes dependent and independent of its catalytic activity. Indeed, the discovery of an ubiquitin-binding domain in HDAC6 (Seigneurin-Berny et al, 2001) led to the unraveling of its participation in cellular functions depending on cell signaling through protein ubiquitination (Kawaguchi et al, 2003;Boyault et al, 2006). HDAC6 therefore appears as a protein functioning at the crossroads between at least two cellular signaling systems, respectively, involving protein lysine acetylation and ubiquitination.…”