Protein aggregates are recruited to aggresome by histone deacetylase 6 via unanchored ubiquitin C termini

Hui Ouyang, Yousuf O. Ali, Mani Ravichandran, Aiping Dong, Wei Qiu, Farrell MacKenzie, Sirano Dhe-Paganon, Cheryl H. Arrowsmith, R. Grace Zhai

Research output: Contribution to journalArticle

115 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2317-2327
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number4
DOIs
StatePublished - Jan 20 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Ouyang, H., Ali, Y. O., Ravichandran, M., Dong, A., Qiu, W., MacKenzie, F., Dhe-Paganon, S., Arrowsmith, C. H., & Zhai, R. G. (2012). Protein aggregates are recruited to aggresome by histone deacetylase 6 via unanchored ubiquitin C termini. Journal of Biological Chemistry, 287(4), 2317-2327. https://doi.org/10.1074/jbc.M111.273730