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 |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:31 |
|---|---|
| Enthalten in: |
Cell reports - 31(2020), 9 vom: 02. Juni, Seite 107680 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
den Brave, Fabian [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 03.05.2021 Date Revised 03.05.2021 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.celrep.2020.107680 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM310720834 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM310720834 | ||
| 003 | DE-627 | ||
| 005 | 20231226201514.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.celrep.2020.107680 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1035.xml |
| 035 | |a (DE-627)NLM310720834 | ||
| 035 | |a (NLM)32492414 | ||
| 035 | |a (PII)S2211-1247(20)30633-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a den Brave, Fabian |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Chaperone-Mediated Protein Disaggregation Triggers Proteolytic Clearance of Intra-nuclear Protein Inclusions |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 03.05.2021 | ||
| 500 | |a Date Revised 03.05.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Apj1 | |
| 650 | 4 | |a Chaperone | |
| 650 | 4 | |a Disaggregation | |
| 650 | 4 | |a Hsp110 | |
| 650 | 4 | |a Hsp40 | |
| 650 | 4 | |a Hsp70 | |
| 650 | 4 | |a Proteostasis | |
| 650 | 4 | |a nucleus | |
| 650 | 4 | |a protein degradation | |
| 650 | 7 | |a APJ1 protein, S cerevisiae |2 NLM | |
| 650 | 7 | |a HSP110 Heat-Shock Proteins |2 NLM | |
| 650 | 7 | |a HSP40 Heat-Shock Proteins |2 NLM | |
| 650 | 7 | |a HSP70 Heat-Shock Proteins |2 NLM | |
| 650 | 7 | |a Heat-Shock Proteins |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a Protein Aggregates |2 NLM | |
| 650 | 7 | |a SIS1 protein, S cerevisiae |2 NLM | |
| 650 | 7 | |a Saccharomyces cerevisiae Proteins |2 NLM | |
| 650 | 7 | |a HsP104 protein, S cerevisiae |2 NLM | |
| 650 | 7 | |a 143012-44-6 |2 NLM | |
| 650 | 7 | |a Proteasome Endopeptidase Complex |2 NLM | |
| 650 | 7 | |a EC 3.4.25.1 |2 NLM | |
| 650 | 7 | |a ATP dependent 26S protease |2 NLM | |
| 650 | 7 | |a EC 3.4.99.- |2 NLM | |
| 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 | |
| 773 | 0 | 8 | |i Enthalten in |t Cell reports |d 2012 |g 31(2020), 9 vom: 02. Juni, Seite 107680 |w (DE-627)NLM217067492 |x 2211-1247 |7 nnns |
| 773 | 1 | 8 | |g volume:31 |g year:2020 |g number:9 |g day:02 |g month:06 |g pages:107680 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.celrep.2020.107680 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 31 |j 2020 |e 9 |b 02 |c 06 |h 107680 | ||