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Elife. 2017 May 2;6. pii: e23759. doi: 10.7554/eLife.23759.

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

Author information

1
Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.
2
Department of Physiology, University of Maryland School of Medicine, Baltimore, United States.
3
Department of Biochemistry and Molecular Biology, Johns Hopkins University, Baltimore, United States.
4
Department of Neuroscience, Johns Hopkins University, Baltimore, United States.
5
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States.
6
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, United States.
7
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, United States.
8
Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, United States.

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 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.

KEYWORDS:

ALS; C. elegans; SOD1; cell biology; cytotoxicity; nuclear export signal; protein misfolding

PMID:
28463106
PMCID:
PMC5449186
DOI:
10.7554/eLife.23759
[Indexed for MEDLINE]
Free PMC Article

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