Document Type

Article

Publication Date

10-24-2016

Keywords

Activin Receptors, Type I, Animals, Antioxidants, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Gastrointestinal Tract, Gene Expression Regulation, Developmental, Humans, Inactivation, Metabolic, Kelch-Like ECH-Associated Protein 1, Longevity, Phosphorylation, RNA Interference, Reactive Oxygen Species, S-Phase Kinase-Associated Proteins, SKP Cullin F-Box Protein Ligases, p38 Mitogen-Activated Protein Kinases

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.

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Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

PLoS Genetics, v. 12, issue 10, art. e1006361

Additional Files

Supporting information.zip (31981 kB)

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