mTORC1-Regulated and HUWE1-Mediated WIPI2 Degradation Controls Autophagy Flux.,Molecular Cell

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mTORC1-Regulated and HUWE1-Mediated WIPI2 Degradation Controls Autophagy Flux.
Molecular Cell ( IF 14.5 ) Pub Date : 2018-10-18 , DOI: 10.1016/j.molcel.2018.09.017
Wei Wan ₁ , Zhiyuan You ₁ , Li Zhou ₁ , Yinfeng Xu ₁ , Chao Peng ₂ , Tianhua Zhou ₁ , Cong Yi ₁ , Yin Shi ₁ , Wei Liu ₃

Affiliation

mTORC1, the major homeostatic sensor and responder, regulates cell catabolism mainly by targeting autophagy. Here, we show that mTORC1 directly controls autophagosome formation via phosphorylation of WIPI2, a critical protein in isolation membrane growth and elongation. mTORC1 phosphorylates Ser395 of WIPI2, directing WIPI2 to interact specifically with the E3 ubiquitin ligase HUWE1 for ubiquitination and proteasomal degradation. Physiological or pharmacological inhibition of mTORC1 in cells promotes WIPI2 stabilization, autophagosome formation, and autophagic degradation. In mouse liver, fasting significantly increases the WIPI2 protein level, while silencing HUWE1 enhances autophagy, and introducing WIPI2 improves lipid clearance. Thus, regulation of the intracellular WIPI2 protein level by mTORC1 and HUWE1 is a key determinant of autophagy flux and may coordinate the initiation, progression, and completion of autophagy.

中文翻译：

mTORC1调节和HUWE1介导的WIPI2降解控制自噬通量。

mTORC1是主要的稳态传感器和响应者，主要通过靶向自噬来调节细胞分解代谢。在这里，我们显示mTORC1通过WIPI2的磷酸化直接控制自噬体的形成，WIPI2是分离膜生长和伸长中的关键蛋白。mTORC1使WIPI2的Ser395磷酸化，指导WIPI2与E3泛素连接酶HUWE1特异性相互作用，以进行泛素化和蛋白酶体降解。细胞中mTORC1的生理或药理抑制作用可促进WIPI2稳定，自噬体形成和自噬降解。在小鼠肝脏中，禁食可显着增加WIPI2蛋白水平，而沉默HUWE1可增强自噬作用，而引入WIPI2可改善脂质清除率。因此，

更新日期：2018-10-18

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