title: Protein aggregates are recruited to aggresome by histone deacetylase 6 via unanchored ubiquitin C termini.
abstract: The aggresome pathway is activated when proteasomal clearance of misfolded proteins is hindered. Misfolded polyubiquitinated protein aggregates are recruited and transported to the aggresome via the microtubule network by a protein complex consisting of histone deacetylase 6 (HDAC6) and the dynein motor complex. The current model suggests that HDAC6 recognizes protein aggregates by binding directly to polyubiquitinated proteins. Here, we show that there are substantial amounts of unanchored ubiquitin in protein aggregates with solvent-accessible C termini. The ubiquitin-binding domain (ZnF-UBP) of HDAC6 binds exclusively to the unanchored C-terminal diglycine motif of ubiquitin instead of conjugated polyubiquitin. The unanchored ubiquitin C termini in the aggregates are generated in situ by aggregate-associated deubiquitinase ataxin-3. These results provide structural and mechanistic bases for the role of HDAC6 in aggresome formation and further suggest a novel ubiquitin-mediated signaling pathway, where the exposure of ubiquitin C termini within protein aggregates enables HDAC6 recognition and transport to the aggresome.
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada. hui.ouyang@utoronto.ca
authors: Hui
authors: H
authors: Ouyang
authors: Yousuf O
authors: YO
authors: Ali
authors: Mani
authors: M
authors: Ravichandran
authors: Aiping
authors: A
authors: Dong
authors: Wei
authors: W
authors: Qiu
authors: Farrell
authors: F
authors: MacKenzie
authors: Sirano
authors: S
authors: Dhe-Paganon
authors: Cheryl H
authors: CH
authors: Arrowsmith
authors: R Grace
authors: RG
authors: Zhai
mesh_terms: D000067699:Ataxin-3; D002460:Cell Line; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D057149:Ubiquitinated Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; D057149:Ubiquitinated Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases