title: The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans.
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.
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Trisha A
authors.initials: TA
authors.lastname: Staab
authors.forename: Trevor C
authors.initials: TC
authors.lastname: Griffen
authors.forename: Connor
authors.initials: C
authors.lastname: Corcoran
authors.forename: Oleg
authors.initials: O
authors.lastname: Evgrafov
authors.forename: James A
authors.initials: JA
authors.lastname: Knowles
authors.forename: Derek
authors.initials: D
authors.lastname: Sieburth
mesh_terms: D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D044842:Cullin Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects; D009154:Mutation; D009420:Nervous System / Q000187:drug effects / Q000378:metabolism; D009469:Neuromuscular Junction / Q000235:genetics / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects*; D017670:Sodium Compounds / Q000494:pharmacology; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018053:Arsenites; D029742:Caenorhabditis elegans Proteins; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; D017670:Sodium Compounds; D014157:Transcription Factors; C073702:skn-1 protein, C elegans; C017947:sodium arsenite
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