Chaperone-mediated protein disaggregation triggers proteolytic clearance of intra-nuclear protein inclusions
The formation of insoluble inclusions in the cytosol and nucleus is associated with impaired protein homeostasis and is a hallmark of several neurodegenerative diseases. Due to the absence of the autophagic machinery, nuclear protein aggregates require a solubilization step preceding degradation by...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
May 26, 2020
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| In: |
Cell reports
Year: 2020, Volume: 31, Issue: 9 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2020.107680 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2020.107680 Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S2211124720306331 
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| Author Notes: | Fabian den Brave, Lucas V. Cairo, Chandhuru Jagadeesan, Carmen Ruger-Herreros, Axel Mogk, Bernd Bukau, Stefan Jentsch |
| Summary: | The formation of insoluble inclusions in the cytosol and nucleus is associated with impaired protein homeostasis and is a hallmark of several neurodegenerative diseases. Due to the absence of the autophagic machinery, nuclear protein aggregates require a solubilization step preceding degradation by the 26S proteasome. Using yeast, we identify a nuclear protein quality control pathway required for the clearance of protein aggregates. The nuclear J-domain protein Apj1 supports protein disaggregation together with Hsp70 but independent of the canonical disaggregase Hsp104. Disaggregation mediated by Apj1/Hsp70 promotes turnover rather than refolding. A loss of Apj1 activity uncouples disaggregation from proteasomal turnover, resulting in accumulation of toxic soluble protein species. Endogenous substrates of the Apj1/Hsp70 pathway include both nuclear and cytoplasmic proteins, which aggregate inside the nucleus upon proteotoxic stress. These findings demonstrate the coordinated activity of the Apj1/Hsp70 disaggregation system with the 26S proteasome in facilitating the clearance of toxic inclusions inside the nucleus. |
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| Item Description: | Gesehen am 01.10.2020 |
| Physical Description: | Online Resource |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2020.107680 |