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Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus
Over 170 different mutations in the gene encoding SOD1 all cause amyotrophic lateral sclerosis (ALS). Available studies have been primarily focused on the mechanisms underlying mutant SOD1 cytotoxicity. How cells defend against the cytotoxicity remains largely unknown. Here, we show that misfolding...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449186/ https://www.ncbi.nlm.nih.gov/pubmed/28463106 http://dx.doi.org/10.7554/eLife.23759 |
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author | Zhong, Yongwang Wang, Jiou Henderson, Mark J Yang, Peixin Hagen, Brian M Siddique, Teepu Vogel, Bruce E Deng, Han-Xiang Fang, Shengyun |
author_facet | Zhong, Yongwang Wang, Jiou Henderson, Mark J Yang, Peixin Hagen, Brian M Siddique, Teepu Vogel, Bruce E Deng, Han-Xiang Fang, Shengyun |
author_sort | Zhong, Yongwang |
collection | PubMed |
description | Over 170 different mutations in the gene encoding SOD1 all cause amyotrophic lateral sclerosis (ALS). Available studies have been primarily focused on the mechanisms underlying mutant SOD1 cytotoxicity. How cells defend against the cytotoxicity remains largely unknown. Here, we show that misfolding of ALS-linked SOD1 mutants and wild-type (wt) SOD1 exposes a normally buried nuclear export signal (NES)-like sequence. The nuclear export carrier protein CRM1 recognizes this NES-like sequence and exports misfolded SOD1 to the cytoplasm. Antibodies against the NES-like sequence recognize misfolded SOD1, but not native wt SOD1 both in vitro and in vivo. Disruption of the NES consensus sequence relocalizes mutant SOD1 to the nucleus, resulting in higher toxicity in cells, and severer impairments in locomotion, egg-laying, and survival in Caenorhabditis elegans. Our data suggest that SOD1 mutants are removed from the nucleus by CRM1 as a defense mechanism against proteotoxicity of misfolded SOD1 in the nucleus. DOI: http://dx.doi.org/10.7554/eLife.23759.001 |
format | Online Article Text |
id | pubmed-5449186 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-54491862017-06-01 Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus Zhong, Yongwang Wang, Jiou Henderson, Mark J Yang, Peixin Hagen, Brian M Siddique, Teepu Vogel, Bruce E Deng, Han-Xiang Fang, Shengyun eLife Cell Biology Over 170 different mutations in the gene encoding SOD1 all cause amyotrophic lateral sclerosis (ALS). Available studies have been primarily focused on the mechanisms underlying mutant SOD1 cytotoxicity. How cells defend against the cytotoxicity remains largely unknown. Here, we show that misfolding of ALS-linked SOD1 mutants and wild-type (wt) SOD1 exposes a normally buried nuclear export signal (NES)-like sequence. The nuclear export carrier protein CRM1 recognizes this NES-like sequence and exports misfolded SOD1 to the cytoplasm. Antibodies against the NES-like sequence recognize misfolded SOD1, but not native wt SOD1 both in vitro and in vivo. Disruption of the NES consensus sequence relocalizes mutant SOD1 to the nucleus, resulting in higher toxicity in cells, and severer impairments in locomotion, egg-laying, and survival in Caenorhabditis elegans. Our data suggest that SOD1 mutants are removed from the nucleus by CRM1 as a defense mechanism against proteotoxicity of misfolded SOD1 in the nucleus. DOI: http://dx.doi.org/10.7554/eLife.23759.001 eLife Sciences Publications, Ltd 2017-05-02 /pmc/articles/PMC5449186/ /pubmed/28463106 http://dx.doi.org/10.7554/eLife.23759 Text en © 2017, Zhong et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Zhong, Yongwang Wang, Jiou Henderson, Mark J Yang, Peixin Hagen, Brian M Siddique, Teepu Vogel, Bruce E Deng, Han-Xiang Fang, Shengyun Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus |
title | Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus |
title_full | Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus |
title_fullStr | Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus |
title_full_unstemmed | Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus |
title_short | Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus |
title_sort | nuclear export of misfolded sod1 mediated by a normally buried nes-like sequence reduces proteotoxicity in the nucleus |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449186/ https://www.ncbi.nlm.nih.gov/pubmed/28463106 http://dx.doi.org/10.7554/eLife.23759 |
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