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Stress-induced NEDDylation promotes cytosolic protein aggregation through HDAC6 in a p62-dependent manner

Stress-coupled NEDDylation potentially regulates the aggregation of nuclear proteins, which could protect the nuclear ubiquitin-proteasome system from proteotoxic stress. However, it remains unclear how NEDDylation controls protein-aggregation responses to diverse stress conditions. Here, we identif...

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Autores principales: Kim, Soyeon, Kwon, Mira, Hwang, Yiseul, Yoon, Junghyun, Park, Sangwook, Kang, Ho Chul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903351/
https://www.ncbi.nlm.nih.gov/pubmed/33665565
http://dx.doi.org/10.1016/j.isci.2021.102146
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author Kim, Soyeon
Kwon, Mira
Hwang, Yiseul
Yoon, Junghyun
Park, Sangwook
Kang, Ho Chul
author_facet Kim, Soyeon
Kwon, Mira
Hwang, Yiseul
Yoon, Junghyun
Park, Sangwook
Kang, Ho Chul
author_sort Kim, Soyeon
collection PubMed
description Stress-coupled NEDDylation potentially regulates the aggregation of nuclear proteins, which could protect the nuclear ubiquitin-proteasome system from proteotoxic stress. However, it remains unclear how NEDDylation controls protein-aggregation responses to diverse stress conditions. Here, we identified HDAC6 as a direct NEDD8-binding partner that regulates the formation of aggresome-like bodies (ALBs) containing NEDDylated cytosolic protein aggregates during ubiquitin stress. HDAC6 colocalizes with stress-induced ALBs, and HDAC6 inhibition suppresses ALBs formation, but not stress-induced NEDDylation, suggesting that HDAC6 carries NEDDylated-proteins to generate ALBs. Then, we monitored the ALBs-associated proteostasis network and found that p62 directly controls ALBs formation as an acceptor of NEDDylated cytosolic aggregates. Interestingly, we also observed that ALBs are highly condensed in chloroquine-treated cells with impaired autophagic flux, indicating that ALBs rely on autophagy. Collectively, our data suggest that NEDD8, HDAC6, and p62 are involved in the management of proteotoxic stress by forming cytosolic ALBs coupled to the aggresome-autophagy flux.
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spelling pubmed-79033512021-03-03 Stress-induced NEDDylation promotes cytosolic protein aggregation through HDAC6 in a p62-dependent manner Kim, Soyeon Kwon, Mira Hwang, Yiseul Yoon, Junghyun Park, Sangwook Kang, Ho Chul iScience Article Stress-coupled NEDDylation potentially regulates the aggregation of nuclear proteins, which could protect the nuclear ubiquitin-proteasome system from proteotoxic stress. However, it remains unclear how NEDDylation controls protein-aggregation responses to diverse stress conditions. Here, we identified HDAC6 as a direct NEDD8-binding partner that regulates the formation of aggresome-like bodies (ALBs) containing NEDDylated cytosolic protein aggregates during ubiquitin stress. HDAC6 colocalizes with stress-induced ALBs, and HDAC6 inhibition suppresses ALBs formation, but not stress-induced NEDDylation, suggesting that HDAC6 carries NEDDylated-proteins to generate ALBs. Then, we monitored the ALBs-associated proteostasis network and found that p62 directly controls ALBs formation as an acceptor of NEDDylated cytosolic aggregates. Interestingly, we also observed that ALBs are highly condensed in chloroquine-treated cells with impaired autophagic flux, indicating that ALBs rely on autophagy. Collectively, our data suggest that NEDD8, HDAC6, and p62 are involved in the management of proteotoxic stress by forming cytosolic ALBs coupled to the aggresome-autophagy flux. Elsevier 2021-02-06 /pmc/articles/PMC7903351/ /pubmed/33665565 http://dx.doi.org/10.1016/j.isci.2021.102146 Text en © 2021 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Kim, Soyeon
Kwon, Mira
Hwang, Yiseul
Yoon, Junghyun
Park, Sangwook
Kang, Ho Chul
Stress-induced NEDDylation promotes cytosolic protein aggregation through HDAC6 in a p62-dependent manner
title Stress-induced NEDDylation promotes cytosolic protein aggregation through HDAC6 in a p62-dependent manner
title_full Stress-induced NEDDylation promotes cytosolic protein aggregation through HDAC6 in a p62-dependent manner
title_fullStr Stress-induced NEDDylation promotes cytosolic protein aggregation through HDAC6 in a p62-dependent manner
title_full_unstemmed Stress-induced NEDDylation promotes cytosolic protein aggregation through HDAC6 in a p62-dependent manner
title_short Stress-induced NEDDylation promotes cytosolic protein aggregation through HDAC6 in a p62-dependent manner
title_sort stress-induced neddylation promotes cytosolic protein aggregation through hdac6 in a p62-dependent manner
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903351/
https://www.ncbi.nlm.nih.gov/pubmed/33665565
http://dx.doi.org/10.1016/j.isci.2021.102146
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