title: Characterization of skn-1/wdr-23 phenotypes in Caenorhabditis elegans; pleiotrophy, aging, glutathione, and interactions with other longevity pathways.
abstract: The SKN-1/Nrf transcription factors are master regulators of oxidative stress responses and are emerging as important determinants of longevity. We previously identified a protein named WDR-23 as a direct repressor of SKN-1 in C. elegans. Loss of wdr-23 influences stress resistance, longevity, development, and reproduction, but it is unknown if WDR-23 influences development and reproduction solely through SKN-1 and the mechanisms by which SKN-1 promotes stress resistance and longevity are poorly defined. Here, we characterize phenotypes of wdr-23 and skn-1 manipulation and explore the role of glutathione. We provide evidence that diverse wdr-23 phenotypes are dependent on SKN-1, that beneficial and detrimental phenotypes of wdr-23 and skn-1 can be partially decoupled, and that SKN-1 activation delays degenerative tissue changes during aging. We also show that total glutathione levels are substantially elevated when the wdr-23/skn-1 pathway is activated and that skn-1 is required for preserving this cellular antioxidant during stress and aging. Alternatively, total glutathione was not elevated in worms with reduced insulin/IGF-1-like signaling or dietary restriction suggesting that SKN-1 ensures longevity via different mechanisms under these conditions. Lastly, genetic interaction data revise our understanding of which skn-1 variants are required for longevity during dietary restriction.
authors.affiliation: Department of Biology and Genetics Institute, University of Florida, Gainesville, FL 32611, United States.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Biology and Genetics Institute, University of Florida, Gainesville, FL 32611, United States. Electronic address: kchoe@ufl.edu.
authors.forename: Keith P
authors.initials: KP
authors.lastname: Choe
mesh_terms: D000818:Animals; D018053:Arsenites / Q000737:chemistry; D049628:Body Size; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism*; D008136:Longevity; D009154:Mutation; D010641:Phenotype; D010858:Pigmentation; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018053:Arsenites; 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; D005978:Glutathione; C015001:arsenite
keywords: Detoxification; Dietary restriction; Nrf2