Chaperone-Mediated Protein Disaggregation Triggers Proteolytic Clearance of Intra-nuclear Protein Inclusions
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved..
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.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2020 |
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Erschienen: |
2020 |
Enthalten in: |
Zur Gesamtaufnahme - volume:31 |
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Enthalten in: |
Cell reports - 31(2020), 9 vom: 02. Juni, Seite 107680 |
Sprache: |
Englisch |
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Beteiligte Personen: |
den Brave, Fabian [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 03.05.2021 Date Revised 03.05.2021 published: Print Citation Status MEDLINE |
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doi: |
10.1016/j.celrep.2020.107680 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM310720834 |
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520 | |a Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved. | ||
520 | |a 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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700 | 1 | |a Cairo, Lucas V |e verfasserin |4 aut | |
700 | 1 | |a Jagadeesan, Chandhuru |e verfasserin |4 aut | |
700 | 1 | |a Ruger-Herreros, Carmen |e verfasserin |4 aut | |
700 | 1 | |a Mogk, Axel |e verfasserin |4 aut | |
700 | 1 | |a Bukau, Bernd |e verfasserin |4 aut | |
700 | 1 | |a Jentsch, Stefan |e verfasserin |4 aut | |
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