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CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1

The ESCRT protein CHMP2B and the RNA-binding protein TDP-43 are both associated with ALS and FTD. The pathogenicity of CHMP2B has mainly been considered a consequence of autophagy–endolysosomal dysfunction, whereas protein inclusions containing phosphorylated TDP-43 are a pathological hallmark of AL...

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Autores principales: Deng, Xue, Sun, Xing, Yue, Wenkai, Duan, Yongjia, Hu, Rirong, Zhang, Kai, Ni, Jiangxia, Cui, Jihong, Wang, Qiangqiang, Chen, Yelin, Li, Ang, Fang, Yanshan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570292/
https://www.ncbi.nlm.nih.gov/pubmed/34726688
http://dx.doi.org/10.1083/jcb.202103033
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author Deng, Xue
Sun, Xing
Yue, Wenkai
Duan, Yongjia
Hu, Rirong
Zhang, Kai
Ni, Jiangxia
Cui, Jihong
Wang, Qiangqiang
Chen, Yelin
Li, Ang
Fang, Yanshan
author_facet Deng, Xue
Sun, Xing
Yue, Wenkai
Duan, Yongjia
Hu, Rirong
Zhang, Kai
Ni, Jiangxia
Cui, Jihong
Wang, Qiangqiang
Chen, Yelin
Li, Ang
Fang, Yanshan
author_sort Deng, Xue
collection PubMed
description The ESCRT protein CHMP2B and the RNA-binding protein TDP-43 are both associated with ALS and FTD. The pathogenicity of CHMP2B has mainly been considered a consequence of autophagy–endolysosomal dysfunction, whereas protein inclusions containing phosphorylated TDP-43 are a pathological hallmark of ALS and FTD. Intriguingly, TDP-43 pathology has not been associated with the FTD-causing CHMP2B(Intron5) mutation. In this study, we identify CHMP2B as a modifier of TDP-43–mediated neurodegeneration in a Drosophila screen. Down-regulation of CHMP2B reduces TDP-43 phosphorylation and toxicity in flies and mammalian cells. Surprisingly, although CHMP2B(Intron5) causes dramatic autophagy dysfunction, disturbance of autophagy does not alter TDP-43 phosphorylation levels. Instead, we find that inhibition of CK1, but not TTBK1/2 (all of which are kinases phosphorylating TDP-43), abolishes the modifying effect of CHMP2B on TDP-43 phosphorylation. Finally, we uncover that CHMP2B modulates CK1 protein levels by negatively regulating ubiquitination and the proteasome-mediated turnover of CK1. Together, our findings propose an autophagy-independent role and mechanism of CHMP2B in regulating CK1 abundance and TDP-43 phosphorylation.
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spelling pubmed-85702922022-07-03 CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1 Deng, Xue Sun, Xing Yue, Wenkai Duan, Yongjia Hu, Rirong Zhang, Kai Ni, Jiangxia Cui, Jihong Wang, Qiangqiang Chen, Yelin Li, Ang Fang, Yanshan J Cell Biol Article The ESCRT protein CHMP2B and the RNA-binding protein TDP-43 are both associated with ALS and FTD. The pathogenicity of CHMP2B has mainly been considered a consequence of autophagy–endolysosomal dysfunction, whereas protein inclusions containing phosphorylated TDP-43 are a pathological hallmark of ALS and FTD. Intriguingly, TDP-43 pathology has not been associated with the FTD-causing CHMP2B(Intron5) mutation. In this study, we identify CHMP2B as a modifier of TDP-43–mediated neurodegeneration in a Drosophila screen. Down-regulation of CHMP2B reduces TDP-43 phosphorylation and toxicity in flies and mammalian cells. Surprisingly, although CHMP2B(Intron5) causes dramatic autophagy dysfunction, disturbance of autophagy does not alter TDP-43 phosphorylation levels. Instead, we find that inhibition of CK1, but not TTBK1/2 (all of which are kinases phosphorylating TDP-43), abolishes the modifying effect of CHMP2B on TDP-43 phosphorylation. Finally, we uncover that CHMP2B modulates CK1 protein levels by negatively regulating ubiquitination and the proteasome-mediated turnover of CK1. Together, our findings propose an autophagy-independent role and mechanism of CHMP2B in regulating CK1 abundance and TDP-43 phosphorylation. Rockefeller University Press 2021-11-02 /pmc/articles/PMC8570292/ /pubmed/34726688 http://dx.doi.org/10.1083/jcb.202103033 Text en © 2021 Deng et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Deng, Xue
Sun, Xing
Yue, Wenkai
Duan, Yongjia
Hu, Rirong
Zhang, Kai
Ni, Jiangxia
Cui, Jihong
Wang, Qiangqiang
Chen, Yelin
Li, Ang
Fang, Yanshan
CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1
title CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1
title_full CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1
title_fullStr CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1
title_full_unstemmed CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1
title_short CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1
title_sort chmp2b regulates tdp-43 phosphorylation and cytotoxicity independent of autophagy via ck1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570292/
https://www.ncbi.nlm.nih.gov/pubmed/34726688
http://dx.doi.org/10.1083/jcb.202103033
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