Article

Direct Inhibition of the Longevity-Promoting Factor SKN-1 by Insulin-like Signaling in C. elegans

Section on Developmental and Stem Cell Biology, Joslin Diabetes Center
Cell (Impact Factor: 33.12). 04/2008; 132(6):1025-38. DOI: 10.1016/j.cell.2008.01.030
Source: PubMed

ABSTRACT Insulin/IGF-1-like signaling (IIS) is central to growth and metabolism and has a conserved role in aging. In C. elegans, reductions in IIS increase stress resistance and longevity, effects that require the IIS-inhibited FOXO protein DAF-16. The C. elegans transcription factor SKN-1 also defends against oxidative stress by mobilizing the conserved phase 2 detoxification response. Here we show that IIS not only opposes DAF-16 but also directly inhibits SKN-1 in parallel. The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1, and reduced IIS leads to constitutive SKN-1 nuclear accumulation in the intestine and SKN-1 target gene activation. SKN-1 contributes to the increased stress tolerance and longevity resulting from reduced IIS and delays aging when expressed transgenically. Furthermore, SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity and is an important direct target of IIS.

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Available from: T Keith Blackwell, Dec 10, 2014
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    • "Interestingly, the mammalian orthologue of the stress-response transcription factor SKN-1, Nrf-2, promotes mitochondrial biogenesis and this requires its translocation to the nucleus [62]. Notably, the nuclear localization of SKN-1 in C. elegans is inhibited by SGK-1 [63], and more recent data has shown that RICT-1/mTORC2 negatively regulates longevity by inhibiting SKN-1/Nrf in the intestine through the SGK-1 kinase, which phosphorylates and inhibits SKN-1 [49]. This could account for the increased mitochondrial content observed in both, rict-1 and sgk-1 depleted animals. "
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    • "In the animal kingdom, many stress transcription factors are utilized during oxidative stress to activate protective responses (bZIP transcription factors X-BOX BINDING PROTEIN1, ACTIVATING TRANSCRIPTION FACTOR4 [ATF4], NF-E2-RELATED FACTOR1-3, and ATF6; An and Blackwell, 2003; Harding et al., 2003; Glover-Cutter et al., 2013), with many of these factors playing intersecting roles in related cellular stresses, including protein homeostasis and aging (Henis-Korenblit et al., 2010; Kenyon, 2010; Hetz, 2012). The intersection of oxidative stress resistance and longevity is a well-researched field in the animal kingdom (Tullet et al., 2008; Ristow and Schmeisser, 2011; Calabrese et al., 2012; Gems and Partridge, 2013), with many stress and longevity pathways conserved in the plant kingdom. For example, micronutritional depravation of essential nutrients is associated with aging and cognitive decline in animal systems (Chen et al., 2013) and growth and mass decline in plant systems. "
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    • ".3% and 91.0% increase in lifespan upon DR and DD, respectively, these increases were only 20.9% and 13.3% in predicted null skn-1 mutants. (D) Under AL liquid conditions, skn-1 mutants' mean lifespan was equal to that of WT, in contrast to results obtained on plates (Tullet et al., 2008). (E, F) pha-4(zu225) mutation eliminated DR longevity in the control smg- 1(cc546ts) background. "
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