rnai screening implicates a skn-1–dependent transcriptional response in stress resistance and longevity deriving from translation inhibitionrnai筛查牵连到skn-1-dependent转录反应压力阻力和长寿源于翻译抑制.pdfVIP

RNAi Screening Implicates a SKN-1–Dependent Transcriptional Response in Stress Resistance and Longevity Deriving from Translation Inhibition Jinling Wang1., Stacey Robida-Stubbs1., Jennifer M. A. Tullet1¤a, Jean-Franc¸ois Rual2,3¤b, Marc Vidal2,3, T. Keith Blackwell1* 1Joslin Diabetes Center, Harvard Stem Cell Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, 3 Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America 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-depende