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

MPG-Autoren
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den Brave,  Fabian
Jentsch, Stefan / Molecular Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Cairo,  Lucas V.
Jentsch, Stefan / Molecular Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Jagadeesan,  Chandhuru
Jentsch, Stefan / Molecular Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Jentsch,  Stefan
Jentsch, Stefan / Molecular Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Zitation

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.


Zitierlink: https://hdl.handle.net/21.11116/0000-0006-A317-8
Zusammenfassung
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.