A coherent FOXO3-SNAI2 feed-forward loop in autophagy

Autophagy is a highly conserved programmed degradation process that regulates a variety of physiological and pathological activities in health, aging, and disease. To identify additional factors that modulate autophagy, we utilized serum-free starvation or Torin1 to induce autophagy in HeLa cells for unbiased mRNA-sequencing analysis and identified SNAI2, a crucial player in epithelial-to-mesenchymal transition and cancer progression, as a regulator of autophagy. Mechanistically, SNAI2 promotes autophagy by physically interacting with FOXO3 and enhancing FOXO3 binding affinity to its response elements in autophagy-related genes. Intriguingly, binding to the DNA targets appears necessary and sufficient for FOXO3 to antagonize its CRM1-dependent nuclear export, illustrating a critical role of DNA in regulating protein nuclear localization. Moreover, stress-elevated SNAI2 expression is mediated by FOXO3, which activates SNAI2 transcription by directly binding to its promoter. Herein, FOXO3 and SNAI2 form a coherent feed-forward regulatory loop to reinforce autophagy genes induction in response to energy stress. Strikingly, a dFoxO-Snail feed-forward circuit also regulates autophagy in Drosophila, suggesting this mechanism is evolutionarily conserved from fly to human.