Abstract
SKN-1/Nrf are the primary antioxidant/detoxification response transcription factors in animals and they promote health and longevity in many contexts. SKN-1/Nrf are activated by a remarkably broad-range of natural and synthetic compounds and physiological conditions. Defining the signaling mechanisms that regulate SKN-1/Nrf activation provides insights into how cells coordinate responses to stress. Nrf2 in mammals is regulated in part by the redox sensor repressor protein named Keap1. In C. elegans, the p38 MAPK cascade in the intestine activates SKN-1 during oxidative stress by promoting its nuclear accumulation. Interestingly, we find variation in the kinetics of p38 MAPK activation and tissues with SKN-1 nuclear accumulation among different pro-oxidants that all trigger strong induction of SKN-1 target genes. Using genome-wide RNAi screening, we identify new genes that are required for activation of the core SKN-1 target gene gst-4 during exposure to the natural pro-oxidant juglone. Among 10 putative activators identified in this screen was skr-1/2, highly conserved homologs of yeast and mammalian Skp1, which function to assemble protein complexes. Silencing of skr-1/2 inhibits induction of SKN-1 dependent detoxification genes and reduces resistance to pro-oxidants without decreasing p38 MAPK activation. Global transcriptomics revealed strong correlation between genes that are regulated by SKR-1/2 and SKN-1 indicating a high degree of specificity. We also show that SKR-1/2 functions upstream of the WD40 repeat protein WDR-23, which binds to and inhibits SKN-1. Together, these results identify a novel p38 MAPK independent signaling mechanism that activates SKN-1 via SKR-1/2 and involves WDR-23.
Highlights
Reactive small molecules are common in natural environments and are produced as byproducts of oxygen metabolism
We provide evidence that the signaling mechanisms that activate SKN-1, a master regulator of detoxification genes and aging in the model organism C. elegans, may vary in response to different oxidative stressors
SKR-1/2 function upstream from SKN-1 and a direct SKN-1 repressor named WDR-23. These results provide new insights into our understanding of SKN-1 regulation and lay the foundation for future studies to define in detail novel signaling pathways that respond to prooxidants
Summary
Reactive small molecules are common in natural environments and are produced as byproducts of oxygen metabolism. Reactive small molecules in excess can cause oxidative damage with widespread detrimental effects, and function as signaling molecules for normal physiological processes [1]. In C. elegans, the cap ‘n’ collar transcription factor family member SKN-1 is homologous to mammalian Nrf and functions to promote longevity and resistance to a wide range of environmental stressors [5]. In response to a wide-range of reactive small molecules, SKN-1/Nrf transcription factors translocate into the nucleus and bind to response elements in target genes to activate a conserved detoxification response [6,7,8]. Additional Keap1-independent signaling mechanisms exist that are lessdefined [9]
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