FOXO-MEDIATED REPRESSION OF DICER-1 REGULATES METABOLISM AND STRESS RESISTANCE IN DROSOPHILA

SÁNCHEZ, JUAN ANDRÉS; INGARAMO, MARÍA CLARA; ANDRES DEKANTY

Congreso; LVIII Annual Meeting of the Argentine Society for Biochemistry and Molecular Biology Research; 2022

The adipose tissue plays an essential role in metabolism and physiology which impacts on animal lifespan and diseasesusceptibility. Dicer-1, a conserved type III endoribonuclease involved in miRNA processing, has been shown to be crucial in thisorgan for the adaptation to nutrient deprivation. However, mechanisms underlying Dcr-1 regulation in response to nutrient andmetabolic challenges and the precise role of Dcr-1 in modulating metabolism, stress responses and aging remain unknown. Herewe provide evidence that Dcr-1 plays a key role in the Drosophila fat body, a functional analog of vertebrate adipose and hepatictissues, in the regulation of metabolism, stress resistance and longevity. We showed that Dcr-1 expression is tightly regulated inthe fat body under different stress types and physiological conditions including starvation, oxidative stress and aging. Fat bodyspecific depletion of Dcr-1 resulted in altered lipid metabolism and increased resistance to oxidative and nutritional stress, while asubstantial extension in lifespan was observed in Dcr-1 heterozygous mutants. We also provide mechanistic evidence showing thatthe transcription factor FOXO regulates Dcr-1 expression upon nutrient deprivation. Under these conditions, JNK-dependentactivation of FOXO in the fat body is required for the repression of Dcr-1 expression and miRNA biogenesis. Chromatinimmunoprecipitation (ChIP) assays revealed that FOXO binds to a conserved DNA binding site in Dcr-1 promoter, thus directlyrepressing its transcription under starvation. The mechanism described here coupling FOXO activation in the adipose tissue to therepression of Dcr-1 implicates a novel and previously uncharacterized function for JNK-FOXO axis integrating nutrient status withmiRNA biogenesis and physiological responses at the organismal level.