Abstract
Transcriptional coordination is a vital process contributing to metabolic homeostasis. As one of the key nodes in the metabolic network, the forkhead transcription factor FOXO has been shown to interact with diverse transcription co-factors and integrate signals from multiple pathways to control metabolism, oxidative stress response, and cell cycle. Recently, insulin/FOXO signaling has been implicated in the regulation of insect development via the interaction with insect hormones, such as ecdysone and juvenile hormone. In this study, we identified an interaction between Drosophila FOXO (dFOXO) and the zinc finger transcription factor Kruppel homolog 1 (Kr-h1), one of the key players in juvenile hormone signaling. We found that Kr-h1 mutants show delayed larval development and altered lipid metabolism, in particular induced lipolysis upon starvation. Notably, Kr-h1 physically and genetically interacts with dFOXO in vitro and in vivo to regulate the transcriptional activation of insulin receptor (InR) and adipose lipase brummer (bmm). The transcriptional co-regulation by Kr-h1 and dFOXO may represent a broad mechanism by which Kruppel-like factors integrate with insulin signaling to maintain metabolic homeostasis and coordinate organism growth.
Highlights
Metabolic homeostasis plays important roles in developing animals1,2
We find that Drosophila Kruppel-like factor Kruppel-like homolog 1 (Kr-h1) acts as a repressor of Drosophila FOXO (dFOXO) to modulate induction of two dFOXO target genes, insulin receptor (InR) and bmm
Like other FOXO interacting partners, Kr-h1 physically binds to dFOXO and inhibits the expression of dFOXO targets by influencing the binding affinity of dFOXO to DNA
Summary
Metabolic homeostasis plays important roles in developing animals. The ability to coordinate growth and development with nutrient availability is critical for the adaptation to fluctuating environment. JH regulates lipid metabolism via the interactions with FOXO in Tsetse flies and diapausing mosquitoes13 Across these studies, it remains unclear how JH interacts with nutrient signaling and whether JH directly acts on FOXO-mediated transcriptional control. In Drosophila, dFOXO interacts with bZIP transcription factor REPTOR of mechanistic target of rapamycin (mTOR) signaling to regulate growth and energy homeostasis. Recent studies found that FOXO interacts with Ultraspiracle (Usp), a co-factor of the ecdysone receptor, to regulate ecdysone biosynthesis and developmental timing in Drosophila. KLF1 is acetylated through its interaction with co-activators p300 and CREB-binding protein (CBP), which leads to elevated induction of target gene beta-globin. The present study suggests a mechanism by which Kruppel-like factor Kr-h1 integrates with insulin/ dFOXO signaling to control lipid metabolism and coordinate organism growth
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