Protein Aggregates Are Recruited to Aggresome by Histone Deacetylase 6 via Unanchored Ubiquitin C Termini
- UHN
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.
- Research Organization:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- Sponsoring Organization:
- FOREIGNINDUSTRYNIH
- OSTI ID:
- 1041340
- Journal Information:
- J. Biol. Chem., Journal Name: J. Biol. Chem. Journal Issue: (4) ; 01, 2012 Vol. 287; ISSN JBCHA3; ISSN 0021-9258
- Country of Publication:
- United States
- Language:
- ENGLISH
Similar Records
Aggresome-like structure induced by isothiocyanates is novel proteasome-dependent degradation machinery
TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase