Abstract
Caenorhabditis elegans SKN-1 (ortholog of mammalian Nrf1/2/3) is critical for oxidative stress resistance and promotes longevity under reduced insulin/IGF-1–like signaling (IIS), dietary restriction (DR), and normal conditions. SKN-1 inducibly activates genes involved in detoxification, protein homeostasis, and other functions in response to stress. Here we used genome-scale RNA interference (RNAi) screening to identify mechanisms that prevent inappropriate SKN-1 target gene expression under non-stressed conditions. We identified 41 genes for which knockdown leads to activation of a SKN-1 target gene (gcs-1) through skn-1-dependent or other mechanisms. These genes correspond to multiple cellular processes, including mRNA translation. Inhibition of translation is known to increase longevity and stress resistance and may be important for DR–induced lifespan extension. One model postulates that these effects derive from reduced energy needs, but various observations suggest that specific longevity pathways are involved. Here we show that translation initiation factor RNAi robustly induces SKN-1 target gene transcription and confers skn-1-dependent oxidative stress resistance. The accompanying increases in longevity are mediated largely through the activities of SKN-1 and the transcription factor DAF-16 (FOXO), which is required for longevity that derives from reduced IIS. Our results indicate that the SKN-1 detoxification gene network monitors various metabolic and regulatory processes. Interference with one of these processes, translation initiation, leads to a transcriptional response whereby SKN-1 promotes stress resistance and functions together with DAF-16 to extend lifespan. This stress response may be beneficial for coping with situations that are associated with reduced protein synthesis.
Highlights
Small molecules that react with proteins, lipids, and nucleic acids can damage cells catastrophically
The nematode C. elegans has proven to be an invaluable organism for elucidating mechanisms that influence aging
We found that many biological processes influence the regulation of SKN-1–dependent stress defenses
Summary
Small molecules that react with proteins, lipids, and nucleic acids can damage cells catastrophically. Oxidative stress refers to damage caused by reactive oxygen species (ROS), but other reactive molecules are produced during metabolism of endogenous (endobiotic) or exogenous (xenobiotic) compounds. Many Phase 2 detoxification genes are induced coordinately in response to oxidative or xenobiotic stress. This stress response is important in the liver and several other tissues in mammals, in which it is mediated by the Nrf1/2/3 (NF-E2-related factor) transcription factors [9,10]. In the nematode C. elegans, this conserved stress response is mediated by the Nrf protein ortholog SKN-1 [11]. In the intestine, which is the major detoxification organ in C. elegans, SKN-1 accumulates in nuclei and activates target genes in response to various stresses [11,12].
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