FOXO mediates organismal hypoxia tolerance by regulating NF-κB inDrosophila

ABSTRACT Exposure of tissues and organs to low oxygen (hypoxia) occurs in both physiological and pathological conditions in animals. Under these conditions, organisms have to adapt their physiology to ensure proper functioning and survival. Here we define a role for the transcription factor FOXO as a mediator of hypoxia tolerance in Drosophila . We find that upon hypoxia exposure, FOXO transcriptional activity is rapidly induced in both larvae and adults. Moreover, we see that foxo mutant animals show misregulated glucose metabolism in low oxygen and subsequently exhibit reduced hypoxia survival. We identify the innate immune transcription factor, NF-KappaB/Relish, as a key FOXO target in the control of hypoxia tolerance. We find that expression of Relish and its target genes are increase in a FOXO-dependent manner in hypoxia, and that relish mutant animals show reduced survival in hypoxia. Together, these data indicate that FOXO is a hypoxia inducible factor that mediates tolerance to low oxygen by inducing immune-like responses.