RRC ID 46448
Author Staab TA, Griffen TC, Corcoran C, Evgrafov O, Knowles JA, Sieburth D.
Title The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans.
Journal PLoS Genet
Abstract 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.
Volume 9(3)
Pages e1003354
Published 2013-3-1
DOI 10.1371/journal.pgen.1003354
PMID 23555279
PMC PMC3605294
MeSH Animals Arsenites / pharmacology Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans* / physiology Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Cell Nucleus / genetics Cell Nucleus / metabolism Cullin Proteins DNA-Binding Proteins* / genetics DNA-Binding Proteins* / metabolism Mitochondrial Membranes / drug effects Mutation Nervous System* / drug effects Nervous System* / metabolism Neuromuscular Junction / genetics Neuromuscular Junction / physiology Oxidative Stress / drug effects* Sodium Compounds / pharmacology Synaptic Transmission / genetics Synaptic Transmission / physiology Transcription Factors* / genetics Transcription Factors* / metabolism
IF 5.175
Times Cited 38
C.elegans tm1817 tm1108