F-Box Protein XREP-4 Is a New Regulator of the Oxidative Stress Response inCaenorhabditis elegans.
The transcription factor SKN-1 (Skinhead family member-1) inCaenorhabditis elegansis a homolog of the mammalian Nrf-2 protein and functions to promote oxidative stress resistance and longevity. SKN-1 mediates protection from reactive oxygen species (ROS) via the transcriptional activation of genes involved in antioxidant defense and phase II detoxification. Although many core regulators of SKN-1 have been identified, much remains unknown about this complex signaling pathway. We carried out an ethyl methanesulfonate (EMS) mutagenesis screen and isolated six independent mutants with attenuated SKN-1-dependent gene activation in response to acrylamide. All six were found to contain mutations in F46F11.6/xrep-4(xenobiotics response pathways-4), which encodes an uncharacterized F-box protein. Loss ofxrep-4inhibits theskn-1-dependent expression of detoxification genes in response to prooxidants and decreases survival of oxidative stress, but does not shorten life span under standard culture conditions. XREP-4 interacts with the ubiquitin ligase component SKR-1 and the SKN-1 principal repressor WDR-23, and knockdown ofxrep-4increases nuclear localization of a WDR-23::GFP fusion protein. Furthermore, a missense mutation in the conserved XREP-4 F-box domain that reduces interaction with SKR-1 but not WDR-23 strongly attenuates SKN-1-dependent gene activation. These results are consistent with XREP-4 influencing the SKN-1 stress response by functioning as a bridge between WDR-23 and the ubiquitin ligase component SKR-1.
Department of Biology, University of Florida, Gainesville, Florida 32611.|Genetics Institute, University of Florida, Gainesville, Florida 32611.
Cheng-Wei
0000-0001-6370-429X
CW
Wu
Department of Biology, University of Florida, Gainesville, Florida 32611.|Genetics Institute, University of Florida, Gainesville, Florida 32611.
Ying
Y
Wang
Department of Biology, University of Florida, Gainesville, Florida 32611 kchoe@ufl.edu.|Genetics Institute, University of Florida, Gainesville, Florida 32611 kchoe@ufl.edu.
Keith P
KP
Choe
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D012097:Repressor Proteins; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C541018:WDR-23 protein, C elegans; C000621184:XREP-4 protein, C elegans; C073702:skn-1 protein, C elegans; D044843:SKP Cullin F-Box Protein Ligases; C522506:SKR-1 protein, C elegans
Nrf-2; SKN-1; aging; detoxification; glutathione; redox; ubiquitin ligase