HDAC6-p97/VCP controlled polyubiquitin chain turnover.
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.
Boyault
Cyril
C
INSERM U309, Laboratoire de Biologie Moléculaire et Cellulaire de la Différenciation, Equipe chromatine et expression des gènes, Institut Albert Bonniot, Faculté de Médecine, Domaine de la Merci, La Tronche, France.
Gilquin
Benoit
B
Zhang
Yu
Y
Rybin
Vladimir
V
Garman
Elspeth
E
Meyer-Klaucke
Wolfram
W
Matthias
Patrick
P
Müller
Christoph W
CW
Khochbin
Saadi
S
D016475:3T3 Cells; D000251:Adenosine Triphosphatases; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000502:physiology*; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D025821:Polyubiquitin / Q000378:metabolism*; D017510:Protein Folding; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D025821:Polyubiquitin; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse