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

• Published in: eLife Vol. 6
• Main Authors: Zhong, Yongwang, Wang, Jiou, Henderson, Mark J, Yang, Peixin, Hagen, Brian M, Siddique, Teepu, Vogel, Bruce E, Deng, Han-Xiang, Fang, Shengyun
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 02.05.2017; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Active Transport, Cell Nucleus; ALS; Amino Acid Motifs; Amyotrophic lateral sclerosis; Animals; Biochemistry; C. elegans; Caenorhabditis elegans; Cell Biology; Conserved sequence; Cytoplasm; Cytotoxicity; DNA sequencing; Egg laying; Exportin 1 Protein; Genetic aspects; Health aspects; Karyopherins - metabolism; Locomotion; Medicine; Methods; Molecular biology; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutant Proteins - toxicity; Mutation; nuclear export signal; Nuclear transport; Pathogenesis; Peptides; Physiology; Protein Binding; Protein Folding; protein misfolding; Protein Sorting Signals; Protein transport; Proteins; Receptors, Cytoplasmic and Nuclear - metabolism; SOD1; Superoxide dismutase; Superoxide Dismutase-1 - chemistry; Superoxide Dismutase-1 - metabolism; Superoxide Dismutase-1 - toxicity; Toxicity; Worms; C. elegans; cell biology; protein misfolding; ALS; nuclear export signal; cytotoxicity; SOD1
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.23759

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 . 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.