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  Chaperone-Mediated Protein Disaggregation Triggers Proteolytic Clearance of Intra-nuclear Protein Inclusions

den Brave, F., Cairo, L. V., Jagadeesan, C., Ruger-Herreros, C., Mogk, A., Bukau, B., et al. (2020). Chaperone-Mediated Protein Disaggregation Triggers Proteolytic Clearance of Intra-nuclear Protein Inclusions. CELL REPORTS, 31(9): UNSP 107680. doi:10.1016/j.celrep.2020.107680.

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 Creators:
den Brave, Fabian1, Author              
Cairo, Lucas V.1, 2, Author              
Jagadeesan, Chandhuru1, 2, Author              
Ruger-Herreros, Carmen3, Author
Mogk, Axel3, Author
Bukau, Bernd3, Author
Jentsch, Stefan1, Author              
Affiliations:
1Jentsch, Stefan / Molecular Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565156              
2Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              
3external, ou_persistent22              

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Free keywords: QUALITY CONTROL DEGRADATION; CYTOSOLIC PROTEINS; HSP70; TARGETS; UBR1; SEQUESTRATION; LOCALIZATION; SUBSTRATE; MECHANISM; MUTANTS
 Abstract: 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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Language(s): eng - English
 Dates: 2020
 Publication Status: Published online
 Pages: 19
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
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Title: CELL REPORTS
Source Genre: Journal
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Publ. Info: 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA : CELL PRESS
Pages: - Volume / Issue: 31 (9) Sequence Number: UNSP 107680 Start / End Page: - Identifier: ISSN: 2211-1247