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| Item Type: | Article |
|---|---|
| Title: | Polyglutamine-rich suppressors of huntingtin toxicity act upstream of hsp70 and sti1 in spatial quality control of amyloid-like proteins |
| Creators Name: | Wolfe, K.J., Ren, H.Y., Trepte, P. and Cyr, D.M. |
| Abstract: | Protein conformational maladies such as Huntington Disease are characterized by accumulation of intracellular and extracellular protein inclusions containing amyloid-like proteins. There is an inverse correlation between proteotoxicity and aggregation, so facilitated protein aggregation appears cytoprotective. To define mechanisms for protective protein aggregation, a screen for suppressors of nuclear huntingtin (Htt103Q) toxicity was conducted. Nuclear Htt103Q is highly toxic and less aggregation prone than its cytosolic form, so we identified suppressors of cytotoxicity caused by Htt103Q tagged with a nuclear localization signal (NLS). High copy suppressors of Htt103Q-NLS toxicity include the polyQ-domain containing proteins Nab3, Pop2, and Cbk1, and each suppresses Htt toxicity via a different mechanism. Htt103Q-NLS appears to inactivate the essential functions of Nab3 in RNA processing in the nucleus. Function of Pop2 and Cbk1 is not impaired by nuclear Htt103Q, as their respective polyQ-rich domains are sufficient to suppress Htt103Q toxicity. Pop2 is a subunit of an RNA processing complex and is localized throughout the cytoplasm. Expression of just the Pop2 polyQ domain and an adjacent proline-rich stretch is sufficient to suppress Htt103Q toxicity. The proline-rich domain in Pop2 resembles an aggresome targeting signal, so Pop2 may act in trans to positively impact spatial quality control of Htt103Q. Cbk1 accumulates in discrete perinuclear foci and overexpression of the Cbk1 polyQ domain concentrates diffuse Htt103Q into these foci, which correlates with suppression of Htt toxicity. Protective action of Pop2 and Cbk1 in spatial quality control is dependent upon the Hsp70 co-chaperone Sti1, which packages amyloid-like proteins into benign foci. Protein:protein interactions between Htt103Q and its intracellular neighbors lead to toxic and protective outcomes. A subset of polyQ-rich proteins buffer amyloid toxicity by funneling toxic aggregation intermediates to the Hsp70/Sti1 system for spatial organization into benign species. |
| Keywords: | Amino Acid Sequence, Amyloidogenic Proteins, Biological Models, Fungal Gene Expression Regulation, HSP70 Heat-Shock Proteins, Heat-Shock Proteins, Huntington Disease, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Nuclear Localization Signals, Nuclear Proteins, Peptides, Plasmids, Protein Aggregates, Protein Binding, Protein Interaction Mapping, Protein-Serine-Threonine Kinases, RNA-Binding Proteins, Ribonucleases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction, Tertiary Protein Structure, Transgenes |
| Source: | PLoS ONE |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Volume: | 9 |
| Number: | 5 |
| Page Range: | e95914 |
| Date: | 14 May 2014 |
| Official Publication: | https://doi.org/10.1371/journal.pone.0095914 |
| PubMed: | View item in PubMed |
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