Regulation of synaptic nlg-1/neuroligin abundance by the skn-1/Nrf stress response pathway protects against oxidative stress.
The Nrf family of transcription factors mediates adaptive responses to stress and longevity, but the identities of the crucial Nrf targets, and the tissues in which they function in multicellular organisms to promote survival, are not known. Here, we use whole transcriptome RNA sequencing to identify 810 genes whose expression is controlled by the SKN-1/Nrf2 negative regulator WDR-23 in the nervous system of Caenorhabditis elegans. Among the genes identified is the synaptic cell adhesion molecule nlg-1/neuroligin. We find that the synaptic abundance of NLG-1 protein increases following pharmacological treatments that generate oxidative stress or by the genetic activation of skn-1. Increasing nlg-1 dosage correlates with increased survival in response to oxidative stress, whereas genetic inactivation of nlg-1 reduces survival and impairs skn-1-mediated stress resistance. We identify a canonical SKN-1 binding site in the nlg-1 promoter that binds to SKN-1 in vitro and is necessary for SKN-1 and toxin-mediated increases in nlg-1 expression in vivo. Together, our results suggest that SKN-1 activation in the nervous system can confer protection to organisms in response to stress by directly regulating nlg-1/neuroligin expression.
Integrative Biology of Disease Graduate Program, University of Southern California, Los Angeles, California, United States of America ; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Trisha A
TA
Staab
Oleg
O
Evgrafov
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Oleg
O
Egrafov
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
James A
JA
Knowles
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Derek
D
Sieburth
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis / Q000235:genetics*; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D008136:Longevity / Q000235:genetics*; D009420:Nervous System / Q000254:growth & development; D018384:Oxidative Stress / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics
D029742:Caenorhabditis elegans Proteins; D015816:Cell Adhesion Molecules, Neuronal; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C093438:neuroligin 1; C073702:skn-1 protein, C elegans