Protein Aggregates Are Recruited to Aggresome by Histone Deacetylase 6 via Unanchored Ubiquitin C Termini

• Published in: The Journal of biological chemistry 2012-01, Vol.287 (4), p.2317-2327
• Main Authors: Ouyang, Hui, Ali, Yousuf O., Ravichandran, Mani, Dong, Aiping, Qiu, Wei, MacKenzie, Farrell, Dhe-Paganon, Sirano, Arrowsmith, Cheryl H., Zhai, R. Grace
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Aggresome; Ataxin-3; BASIC BIOLOGICAL SCIENCES; Cell Line; CLEARANCE; Deubiquitination; Histone Deacetylase 6; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; HISTONES; Humans; MICROTUBULES; MOTORS; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Aggregation; PROTEIN STRUCTURE; Protein Structure and Folding; Protein Structure, Tertiary; Protein Transport - physiology; Protein-Protein Interactions; PROTEINS; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction - physiology; TRANSPORT; Ubiquitin; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitinated Proteins - genetics; Ubiquitinated Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.273730

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. Background: Misfolded protein aggregates are recruited to the aggresome by a protein complex consisting of histone deacetylase 6 (HDAC6). Results: The ubiquitin-binding domain (ZnF-UBP) of HDAC6 binds to ubiquitin C termini generated by ataxin-3. Conclusion: The exposure of ubiquitin C termini within protein aggregates enables HDAC6 recognition. Significance: This study provides the role of HDAC6 in aggresome formation and suggests a novel ubiquitin-mediated signaling pathway.