A coherent FOXO3-SNAI2 feed-forward loop in autophagy
Xiaowei Guo, Zhuojie Li, Xiaojie Zhu, Meixiao Zhan, Chenxi Wu, Xiang Ding, Kai Peng, Wenzhe Li, Xianjue Ma, Zhongwei Lv, Ligong Lu, Lei Xue
Abstract
Significance Understanding 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 Drosophila , suggesting this evolutionarily conserved regulatory loop is engaged in more physiological activities.