The C. elegans insulin receptor ortholog
daf-2 promotes reproductive development and controls lifespan by regulating nuclear translocation of the FoxO transcription factor DAF-16 via a conserved PI 3-kinase/AKT pathway. Nuclear localization of DAF-16/FoxO is necessary but not sufficient for full DAF-16/FoxO activity, suggesting that other inputs regulate the activity of nuclear DAF-16/FoxO. We recently discovered the EAK (enhancer-of
akt-1) pathway, which acts in parallel to AKT-1 to inhibit nuclear DAF-16/FoxO activity. Similar to mutation of other eak genes, mutations in the novel conserved gene
eak-7 enhance the dauer arrest phenotype of
akt-1 null mutants and increase mRNA levels of direct DAF-16/FoxO target genes such as
sod-3 in
akt-1 null mutants. However, in contrast to other EAK pathway components, which do not promote longevity when mutated,
eak-7 mutation extends lifespan by ~25% and promotes stress resistance in a DAF-16/FoxO-dependent manner. Whereas
daf-16/FoxO mRNA levels and DAF-16::GFP subcellular localization are unaffected by
eak-7 mutation, DAF-16/FoxO protein levels are elevated in
eak-7;
akt-1 double mutants compared to
akt-1 single mutants, suggesting that EAK-7 inhibits DAF-16/FoxO activity at least in part by reducing steady-state DAF-16/FoxO protein levels. A functional EAK-7::GFP transgene is expressed in multiple tissues, including vulva, intestine, neurons, and the endocrine XXX cells. Tissue-specific expression experiments demonstrate that EAK-7 acts nonautonomously to control both lifespan and dauer arrest. Our results are consistent with a model whereby EAK-7 and AKT-1 act via distinct and complementary mechanisms to inhibit DAF-16/FoxO activity. EAK-7 and Akt/PKB may act similarly to regulate FoxO transcription factor activity in mammals.