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.