Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus
Yongwang Zhong,
Jiou Wang,
Mark J Henderson,
Peixin Yang,
Brian M Hagen,
Teepu Siddique,
Bruce E Vogel,
Han-Xiang Deng,
Shengyun Fang
Affiliations
Yongwang Zhong
Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States; Department of Physiology, University of Maryland School of Medicine, Baltimore, United States
Jiou Wang
Department of Biochemistry and Molecular Biology, Johns Hopkins University, Baltimore, United States; Department of Neuroscience, Johns Hopkins University, Baltimore, United States
Mark J Henderson
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
Peixin Yang
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, United States; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, United States
Brian M Hagen
Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States; Department of Physiology, University of Maryland School of Medicine, Baltimore, United States
Teepu Siddique
Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, United States
Bruce E Vogel
Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States; Department of Physiology, University of Maryland School of Medicine, Baltimore, United States
Han-Xiang Deng
Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, United States
Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States; Department of Physiology, University of Maryland School of Medicine, Baltimore, United States; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, United States
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.
