14-3-3 Epsilon antagonizes FoxO to control growth, apoptosis and longevity in Drosophila.
Antagonism between growth-promoting and stress-responsive signaling influences tissue homeostasis and longevity in metazoans. The transcription factor FoxO is central to this regulation, affecting cell proliferation, stress responses, apoptosis, and longevity. Insulin/IGF signaling promotes FoxO phosphorylation, causing its interaction with 14-3-3 molecules. The consequences of this interaction for FoxO-induced biological processes and for the regulation of lifespan in higher organisms remain unclear. Significant complexities in the effects of 14-3-3 proteins on lifespan have been uncovered in Caenorhabditis elegans, suggesting both positive and negative roles for 14-3-3 proteins in the control of aging. Using genetic and biochemical studies, we show here that 14-3-3epsilon antagonizes FoxO function in Drosophila. We find that dFoxO and 14-3-3epsilon proteins interact in vivo and that this interaction is lost in response to oxidative stress. Loss of 14-3-3epsilon results in increased stress-induced apoptosis, growth repression and extended lifespan of flies, phenotypes associated with elevated FoxO function. Our results further show that increased expression of 14-3-3epsilon reverts FoxO-induced growth defects. 14-3-3epsilon thus serves as a central modulator of FoxO activity in the regulation of growth, cell death and longevity in vivo.
Nielsen
Mette Damgaard
MD
Department of Biology, University of Rochester, Rochester, NY 14627, USA.
Luo
Xi
X
Biteau
Benoît
B
Syverson
Keith
K
Jasper
Heinrich
H
D048948:14-3-3 Proteins / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics / Q000254:growth & development*; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008297:Male; D018384:Oxidative Stress / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology; D012160:Retina / Q000254:growth & development / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D048948:14-3-3 Proteins; D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D020033:Protein Isoforms