1. Cell Biology

Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus

  1. Yongwang Zhong
  2. Jiou Wang
  3. Mark J Henderson
  4. Peixin Yang
  5. Brian M Hagen
  6. Teepu Siddique
  7. Bruce E Vogel
  8. Han-Xiang Deng
  9. Shengyun Fang  Is a corresponding author
  1. University of Maryland School of Medicine, United States
  2. Johns Hopkins University, United States
  3. National Institutes of Health, United States
  4. Northwestern University Feinberg School of Medicine, United States
https://doi.org/10.7554/eLife.23759
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Cite this article
  1. Yongwang Zhong
  2. Jiou Wang
  3. Mark J Henderson
  4. Peixin Yang
  5. Brian M Hagen
  6. Teepu Siddique
  7. Bruce E Vogel
  8. Han-Xiang Deng
  9. Shengyun Fang
(2017)
Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus
eLife 6:e23759.
https://doi.org/10.7554/eLife.23759
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Abstract

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 C. 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.

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Author details

  1. Yongwang Zhong

    Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Jiou Wang

    Department of Biochemistry and Molecular Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Mark J Henderson

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Peixin Yang

    Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Brian M Hagen

    Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Teepu Siddique

    Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Bruce E Vogel

    Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Han-Xiang Deng

    Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Shengyun Fang

    Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States
    For correspondence
    sfang@umaryland.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7280-5463

Funding

National Science Foundation (1120833)

  • Shengyun Fang

National Institute on Alcohol Abuse and Alcoholism (R21AA024245)

  • Shengyun Fang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Ramanujan S Hegde, MRC Laboratory of Molecular Biology, United Kingdom

Version history

  1. Received: November 29, 2016
  2. Accepted: April 30, 2017
  3. Accepted Manuscript published: May 2, 2017 (version 1)
  4. Version of Record published: May 30, 2017 (version 2)

Copyright

© 2017, Zhong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yongwang Zhong
  2. Jiou Wang
  3. Mark J Henderson
  4. Peixin Yang
  5. Brian M Hagen
  6. Teepu Siddique
  7. Bruce E Vogel
  8. Han-Xiang Deng
  9. Shengyun Fang
(2017)
Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus
eLife 6:e23759.
https://doi.org/10.7554/eLife.23759

Share this article

https://doi.org/10.7554/eLife.23759

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