The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans.
The Nrf family of transcription factors plays a critical role in mediating adaptive responses to cellular stress and defends against neurodegeneration, aging, and cancer. Here, we report a novel role for the Caenorhabditis elegans Nrf homolog SKN-1 in regulating synaptic transmission at neuromuscula...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-03-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3605294?pdf=render |
| _version_ | 1817978998035054592 |
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| author | Trisha A Staab Trevor C Griffen Connor Corcoran Oleg Evgrafov James A Knowles Derek Sieburth |
| author_facet | Trisha A Staab Trevor C Griffen Connor Corcoran Oleg Evgrafov James A Knowles Derek Sieburth |
| author_sort | Trisha A Staab |
| collection | DOAJ |
| description | The Nrf family of transcription factors plays a critical role in mediating adaptive responses to cellular stress and defends against neurodegeneration, aging, and cancer. Here, we report a novel role for the Caenorhabditis elegans Nrf homolog SKN-1 in regulating synaptic transmission at neuromuscular junctions (NMJs). Activation of SKN-1, either by acute pharmacological treatment with the mitochondrial toxin sodium arsenite or by mutations that cause constitutive SKN-1 activation, results in defects in neuromuscular function. Additionally, elimination of the conserved WD40 repeat protein WDR-23, a principal negative regulator of SKN-1, results in impaired locomotion and synaptic vesicle and neuropeptide release from cholinergic motor axons. Mutations that abolish skn-1 activity restore normal neuromuscular function to wdr-23 mutants and animals treated with toxin. We show that negative regulation of SKN-1 by WDR-23 in the intestine, but not at neuromuscular junctions, is necessary and sufficient for proper neuromuscular function. WDR-23 isoforms differentially localize to the outer membranes of mitochondria and to nuclei, and the effects of WDR-23 on neuromuscular function are dependent on its interaction with cullin E3 ubiquitin ligase. Finally, whole-transcriptome RNA sequencing of wdr-23 mutants reveals an increase in the expression of known SKN-1/Nrf2-regulated stress-response genes, as well as neurotransmission genes not previously implicated in SKN-1/Nrf2 responses. Together, our results indicate that SKN-1/Nrf2 activation may be a mechanism through which cellular stress, detected in one tissue, affects cellular function of a distal tissue through endocrine signaling. These results provide insight into how SKN-1/Nrf2 might protect the nervous system from damage in response to oxidative stress. |
| first_indexed | 2024-04-13T22:36:11Z |
| format | Article |
| id | doaj.art-672b17774d40470f815bed17bb5c7647 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-13T22:36:11Z |
| publishDate | 2013-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-672b17774d40470f815bed17bb5c76472022-12-22T02:26:45ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-03-0193e100335410.1371/journal.pgen.1003354The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans.Trisha A StaabTrevor C GriffenConnor CorcoranOleg EvgrafovJames A KnowlesDerek SieburthThe Nrf family of transcription factors plays a critical role in mediating adaptive responses to cellular stress and defends against neurodegeneration, aging, and cancer. Here, we report a novel role for the Caenorhabditis elegans Nrf homolog SKN-1 in regulating synaptic transmission at neuromuscular junctions (NMJs). Activation of SKN-1, either by acute pharmacological treatment with the mitochondrial toxin sodium arsenite or by mutations that cause constitutive SKN-1 activation, results in defects in neuromuscular function. Additionally, elimination of the conserved WD40 repeat protein WDR-23, a principal negative regulator of SKN-1, results in impaired locomotion and synaptic vesicle and neuropeptide release from cholinergic motor axons. Mutations that abolish skn-1 activity restore normal neuromuscular function to wdr-23 mutants and animals treated with toxin. We show that negative regulation of SKN-1 by WDR-23 in the intestine, but not at neuromuscular junctions, is necessary and sufficient for proper neuromuscular function. WDR-23 isoforms differentially localize to the outer membranes of mitochondria and to nuclei, and the effects of WDR-23 on neuromuscular function are dependent on its interaction with cullin E3 ubiquitin ligase. Finally, whole-transcriptome RNA sequencing of wdr-23 mutants reveals an increase in the expression of known SKN-1/Nrf2-regulated stress-response genes, as well as neurotransmission genes not previously implicated in SKN-1/Nrf2 responses. Together, our results indicate that SKN-1/Nrf2 activation may be a mechanism through which cellular stress, detected in one tissue, affects cellular function of a distal tissue through endocrine signaling. These results provide insight into how SKN-1/Nrf2 might protect the nervous system from damage in response to oxidative stress.http://europepmc.org/articles/PMC3605294?pdf=render |
| spellingShingle | Trisha A Staab Trevor C Griffen Connor Corcoran Oleg Evgrafov James A Knowles Derek Sieburth The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans. PLoS Genetics |
| title | The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans. |
| title_full | The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans. |
| title_fullStr | The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans. |
| title_full_unstemmed | The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans. |
| title_short | The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans. |
| title_sort | conserved skn 1 nrf2 stress response pathway regulates synaptic function in caenorhabditis elegans |
| url | http://europepmc.org/articles/PMC3605294?pdf=render |
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