Protein aggregates are recruited to aggresome by histone deacetylase 6 via unanchored ubiquitin C termini.
Protein aggregates are recruited to aggresome by histone deacetylase 6 via unanchored ubiquitin C termini.
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DOI：
10.1074/jbc.m111.273730
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发表时间：
2012-01-20
期刊：
影响因子：
--
通讯作者：
Zhai RG
中科院分区：
文献类型：
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作者：
Ouyang H;Ali YO;Ravichandran M;Dong A;Qiu W;MacKenzie F;Dhe-Paganon S;Arrowsmith CH;Zhai RG
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. 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.
