Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans.
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.
Tullet
Jennifer M A
JM
Section on Developmental and Stem Cell Biology, Joslin Diabetes Center; Department of Pathology, Harvard Medical School; Harvard Stem Cell Institute, 1 Joslin Place, Boston, MA 02215, USA.
Hertweck
Maren
M
An
Jae Hyung
JH
Baker
Joseph
J
Hwang
Ji Yun
JY
Liu
Shu
S
Oliveira
Riva P
RP
Baumeister
Ralf
R
Blackwell
T Keith
TK
D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053263:Gene Regulatory Networks; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007422:Intestines; D008136:Longevity; D018384:Oxidative Stress; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D014157:Transcription Factors; C073702:skn-1 protein, C elegans; D007334:Insulin-Like Growth Factor I; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin