title: A negative-feedback loop between the detoxification/antioxidant response factor SKN-1 and its repressor WDR-23 matches organism needs with environmental conditions.
abstract: Negative-feedback loops between transcription factors and repressors in responses to xenobiotics, oxidants, heat, hypoxia, DNA damage, and infection have been described. Although common, the function of feedback is largely unstudied. Here, we define a negative-feedback loop between the Caenorhabditis elegans detoxification/antioxidant response factor SKN-1/Nrf and its repressor wdr-23 and investigate its function in vivo. Although SKN-1 promotes stress resistance and longevity, we find that tight regulation by WDR-23 is essential for growth and reproduction. By disabling SKN-1 transactivation of wdr-23, we reveal that feedback is required to set the balance between growth/reproduction and stress resistance/longevity. We also find that feedback is required to set the sensitivity of a core SKN-1 target gene to an electrophile. Interestingly, the effect of feedback on target gene induction is greatly reduced when the stress response is strongly activated, presumably to ensure maximum activation of cytoprotective genes during potentially fatal conditions. Our work provides a framework for understanding the function of negative feedback in inducible stress responses and demonstrates that manipulation of feedback alone can shift the balance of competing animal processes toward cell protection, health, and longevity.
authors.affiliation: Department of Biology and Genetics Institute, University of Florida, Gainesville, Florida, USA.
authors.forename: Chi K
authors.initials: CK
authors.lastname: Leung
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Andrew
authors.initials: A
authors.lastname: Deonarine
authors.forename: Lanlan
authors.initials: L
authors.lastname: Tang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Prasse
authors.forename: Keith P
authors.initials: KP
authors.lastname: Choe
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D019610:Cytoprotection; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D008136:Longevity; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012098:Reproduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C541018:WDR-23 protein, C elegans; C073702:skn-1 protein, C elegans