Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans.

Authors: Tullet JM; Hertweck M; An JH; Baker J; Hwang JY; Liu S; Oliveira RP; Baumeister R; Blackwell TK

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.

Keywords: Animals; Caenorhabditis elegans/*physiology; Caenorhabditis elegans Proteins/*metabolism; DNA-Binding Proteins/*metabolism; Gene Regulatory Networks; Insulin/metabolism; Insulin-Like Growth Factor I/metabolism; Intestines; Longevity; Oxidative Stress; Phosphorylation; Receptor, Insulin/metabolism; *Signal Transduction; Transcription Factors/*metabolism
Journal: Cell
Volume: 132
Issue: 6
Pages: 1025-38
Date: March 25, 2008
PMID: 18358814
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Tullet JM, Hertweck M, An JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, Blackwell TK (2008) Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132: 1025-38.

Study Lifespan Factors:
  • skn-1 SKiNhead 1

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