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...

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Published ineLife 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
LanguageEnglish
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
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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 . 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.
AbstractList 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: eLife digest Amyotrophic lateral sclerosis (ALS) is a disease that leads to muscle weakness and paralysis. The symptoms become progressively worse over time to the point that patients die because they become unable to breathe. Over 170 different genetic mistakes (or mutations) in a gene that encodes a protein called SOD1 are known to cause ALS. These mutations cause the SOD1 protein to form different shapes that are toxic to nerve cells, leading to the gradual loss of the nerve cells that control movement. SOD1 is normally found in a compartment within nerve cells called the nucleus, which is where most of the cell's genetic information is stored and managed. A nematode worm called Caenorhabditis elegans has often been used as a model to study the role of SOD1 in ALS because its nervous system shares many features in common with ours but is much smaller. Some evidence suggests that cells may be able to defend themselves against the harmful effects of abnormal SOD1 proteins. However, it is not clear how these defences might work. Zhong et al. examined variants of SOD1 proteins from human cells grown in a laboratory. The experiments show that some mutant SOD1 proteins fold in such a way that a small section of the protein that is normally buried within the protein's structure is exposed on the surface. Mutant SOD1 proteins that expose this "peptide" are removed from the nucleus and are linked with faster progression of ALS in patients. Further experiments show that another protein called CRM1 can recognise this exposed peptide, leading to the removal of the mutant SOD1 proteins from the nucleus. Zhong et al. found that if mutant SOD1 is not removed from the nucleus of nerve cells, the nematode worms developed ALS symptoms even faster. These findings suggest that cells may be able to remove some mutant SOD1 proteins from the nucleus to defend themselves against the proteins' toxic effects. Future work will reveal whether other cells use this approach to protect themselves against other diseases. The peptide discovered in this work may also have the potential to be used as a marker to predict how individual cases of ALS will progress, or as a target for treatments against the disease. DOI:
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.
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.
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. Amyotrophic lateral sclerosis (ALS) is a disease that leads to muscle weakness and paralysis. The symptoms become progressively worse over time to the point that patients die because they become unable to breathe. Over 170 different genetic mistakes (or mutations) in a gene that encodes a protein called SOD1 are known to cause ALS. These mutations cause the SOD1 protein to form different shapes that are toxic to nerve cells, leading to the gradual loss of the nerve cells that control movement. SOD1 is normally found in a compartment within nerve cells called the nucleus, which is where most of the cell’s genetic information is stored and managed. A nematode worm called Caenorhabditis elegans has often been used as a model to study the role of SOD1 in ALS because its nervous system shares many features in common with ours but is much smaller. Some evidence suggests that cells may be able to defend themselves against the harmful effects of abnormal SOD1 proteins. However, it is not clear how these defences might work. Zhong et al. examined variants of SOD1 proteins from human cells grown in a laboratory. The experiments show that some mutant SOD1 proteins fold in such a way that a small section of the protein that is normally buried within the protein’s structure is exposed on the surface. Mutant SOD1 proteins that expose this “peptide” are removed from the nucleus and are linked with faster progression of ALS in patients. Further experiments show that another protein called CRM1 can recognise this exposed peptide, leading to the removal of the mutant SOD1 proteins from the nucleus. Zhong et al. found that if mutant SOD1 is not removed from the nucleus of nerve cells, the nematode worms developed ALS symptoms even faster. These findings suggest that cells may be able to remove some mutant SOD1 proteins from the nucleus to defend themselves against the proteins’ toxic effects. Future work will reveal whether other cells use this approach to protect themselves against other diseases. The peptide discovered in this work may also have the potential to be used as a marker to predict how individual cases of ALS will progress, or as a target for treatments against the disease.
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
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 Amyotrophic lateral sclerosis (ALS) is a disease that leads to muscle weakness and paralysis. The symptoms become progressively worse over time to the point that patients die because they become unable to breathe. Over 170 different genetic mistakes (or mutations) in a gene that encodes a protein called SOD1 are known to cause ALS. These mutations cause the SOD1 protein to form different shapes that are toxic to nerve cells, leading to the gradual loss of the nerve cells that control movement. SOD1 is normally found in a compartment within nerve cells called the nucleus, which is where most of the cell’s genetic information is stored and managed. A nematode worm called Caenorhabditis elegans has often been used as a model to study the role of SOD1 in ALS because its nervous system shares many features in common with ours but is much smaller. Some evidence suggests that cells may be able to defend themselves against the harmful effects of abnormal SOD1 proteins. However, it is not clear how these defences might work. Zhong et al. examined variants of SOD1 proteins from human cells grown in a laboratory. The experiments show that some mutant SOD1 proteins fold in such a way that a small section of the protein that is normally buried within the protein’s structure is exposed on the surface. Mutant SOD1 proteins that expose this “peptide” are removed from the nucleus and are linked with faster progression of ALS in patients. Further experiments show that another protein called CRM1 can recognise this exposed peptide, leading to the removal of the mutant SOD1 proteins from the nucleus. Zhong et al. found that if mutant SOD1 is not removed from the nucleus of nerve cells, the nematode worms developed ALS symptoms even faster. These findings suggest that cells may be able to remove some mutant SOD1 proteins from the nucleus to defend themselves against the proteins’ toxic effects. Future work will reveal whether other cells use this approach to protect themselves against other diseases. The peptide discovered in this work may also have the potential to be used as a marker to predict how individual cases of ALS will progress, or as a target for treatments against the disease. DOI: http://dx.doi.org/10.7554/eLife.23759.002
Audience Academic
Author Hagen, Brian M
Fang, Shengyun
Zhong, Yongwang
Siddique, Teepu
Deng, Han-Xiang
Wang, Jiou
Henderson, Mark J
Vogel, Bruce E
Yang, Peixin
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  orcidid: 0000-0001-7280-5463
  surname: Fang
  fullname: Fang, Shengyun
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/28463106$$D View this record in MEDLINE/PubMed
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Keywords C. elegans
cell biology
protein misfolding
ALS
nuclear export signal
cytotoxicity
SOD1
Language English
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SSID ssj0000748819
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Snippet Over 170 different mutations in the gene encoding SOD1 all cause amyotrophic lateral sclerosis (ALS). Available studies have been primarily focused on the...
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SubjectTerms 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
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Title Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus
URI https://www.ncbi.nlm.nih.gov/pubmed/28463106
https://www.proquest.com/docview/1952734688
https://pubmed.ncbi.nlm.nih.gov/PMC5449186
https://doaj.org/article/7385a4b9f6ca41dc809a49f0ef1d3d6e
Volume 6
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