biostudies-literatureGuo XShanghai Committee of Science and TechnologyNational Natural Science Foundation of ChinaChina Postdoctoral Science FoundationShanghai Shenkang Three Years Action Projecte2118285119https://www.ebi.ac.uk/biostudies/studies/S-EPMC8931368biostudies-literatureUnknown119(11)SignificanceUnderstanding autophagy regulation is instrumental in developing therapeutic interventions for autophagy-associated disease. Here, we identified SNAI2 as a regulator of autophagy from a genome-wide screen in HeLa cells. Upon energy stress, SNAI2 is transcriptionally activated by FOXO3 and interacts with FOXO3 to form a feed-forward regulatory loop to reinforce the expression of autophagy genes. Of note, SNAI2-increased FOXO3-DNA binding abrogates CRM1-dependent FOXO3 nuclear export, illuminating a pivotal role of DNA in the nuclear retention of nucleocytoplasmic shuttling proteins. Moreover, a dFoxO-Snail feed-forward loop regulates both autophagy and cell size in <i>Drosophila</i>, suggesting this evolutionarily conserved regulatory loop is engaged in more physiological activities.Proceedings of the National Academy of Sciences of the United States of AmericaA coherent FOXO3-SNAI2 feed-forward loop in autophagy.PMC893136832000547200022907109DZ226010081771957SHDC2020CR2054B31970536Li WLv ZLu LDing XLi ZZhan MGuo XWu CMa XZhu XXue LPeng KfalseA coherent FOXO3-SNAI2 feed-forward loop in autophagy.SignificanceUnderstanding autophagy regulation is instrumental in developing therapeutic interventions for autophagy-associated disease. Here, we identified SNAI2 as a regulator of autophagy from a genome-wide screen in HeLa cells. Upon energy stress, SNAI2 is transcriptionally activated by FOXO3 and interacts with FOXO3 to form a feed-forward regulatory loop to reinforce the expression of autophagy genes. Of note, SNAI2-increased FOXO3-DNA binding abrogates CRM1-dependent FOXO3 nuclear export, illuminating a pivotal role of DNA in the nuclear retention of nucleocytoplasmic shuttling proteins. Moreover, a dFoxO-Snail feed-forward loop regulates both autophagy and cell size in <i>Drosophila</i>, suggesting this evolutionarily conserved regulatory loop is engaged in more physiological activities.2022-01-01T00:00:00Z2022 Mar2025-04-21T23:18:53.029Z2025-04-05T19:06:03.56ZS-EPMC89313683527139010.1073/pnas.2118285119