A coherent FOXO3-SNAI2 feed-forward loop in autophagy.
A coherent FOXO3-SNAI2 feed-forward loop in autophagy.
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DOI：
10.1073/pnas.2118285119
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发表时间：
2022-03-15
影响因子：
11.1
通讯作者：
Xue L
中科院分区：
文献类型：
--
作者：
Guo X;Li Z;Zhu X;Zhan M;Wu C;Ding X;Peng K;Li W;Ma X;Lv Z;Lu L;Xue L
了解自噬调节有助于开发针对自噬相关疾病的治疗干预措施。在这里，我们从HeLa细胞的全基因组筛选中确定SNAI2是自噬的调节因子。在能量胁迫下，SNAI2被FOXO_3转录激活，并与FOXO_3相互作用形成前馈调控环，增强自噬基因的表达。值得注意的是，SNAI2增加的FOXO_3-DNA结合取消了CRM1依赖的FOXO_3核输出，说明DNA在核质穿梭蛋白的核保留中起着关键作用。此外，dFOXO-Snail前馈环同时调节果蝇的自噬和细胞大小，表明这个进化上保守的调节环参与了更多的生理活动。自噬是一种高度保守的程序性降解过程，调节健康、衰老和疾病中的各种生理和病理活动。为了确定调节自噬的其他因素，我们利用无血清饥饿或Torin1在HeLa细胞中诱导自噬进行无偏见的mRNA测序分析，并确定SNAI2，在上皮向间充质转化和癌症进展中起关键作用，作为自噬的调节因子。在机制上，SNAI2通过与FOXO_3的物理相互作用促进自噬，并在自噬相关基因中增强FOXO_3与其反应元件的亲和力。有趣的是，与DNA靶标的结合似乎是FOX03拮抗其依赖CRM1的核出口的必要条件和充分条件，这说明了DNA在调节蛋白质核定位方面的关键作用。此外，应激增强的SNAI2表达是由FOXO_3介导的，FOXO_3通过直接与其启动子结合来激活SNAI2转录。在此，FOX03和SNAI2形成了一个连贯的前馈调控环，以加强自噬基因对能量胁迫的诱导。引人注目的是，dFOXO-Snail前馈回路也调节果蝇的自噬，这表明这种机制在进化上是从苍蝇到人类的保守。
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. 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.
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影响因子：
4.5
作者：
Bai H;Kang P;Hernandez AM;Tatar M
通讯作者：
Tatar M
排序Nexin 5介导病毒诱导的自噬和免疫力。
影响因子：
64.8
作者：
Dong X;Yang Y;Zou Z;Zhao Y;Ci B;Zhong L;Bhave M;Wang L;Kuo YC;Zang X;Zhong R;Aguilera ER;Richardson RB;Simonetti B;Schoggins JW;Pfeiffer JK;Yu L;Zhang X;Xie Y;Schmid SL;Xiao G;Gleeson PA;Ktistakis NT;Cullen PJ;Xavier RJ;Levine B
通讯作者：
Levine B
影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
16.6
作者：
Cho YS;Zhu J;Li S;Wang B;Han Y;Jiang J
通讯作者：
Jiang J
影响因子：
3.2
作者：
Boccitto M;Kalb RG
通讯作者：
Kalb RG