mTORC1-Regulated and HUWE1-Mediated WIPI2 Degradation Controls Autophagy Flux
mTORC1-Regulated and HUWE1-Mediated WIPI2 Degradation Controls Autophagy Flux
复制标题
mTORC1 调节和 HUWE1 介导的 WIPI2 降解控制自噬通量
DOI：
10.1016/j.molcel.2018.09.017
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发表时间：
2018-10-18
期刊：
影响因子：
16
通讯作者：
Liu, Wei
中科院分区：
文献类型：
--
作者：
Wan, Wei;You, Zhiyuan;Liu, Wei
mTORC1是主要的稳态传感器和应答器，主要通过靶向自噬来调节细胞catalytic。在这里，我们发现mTORC 1通过磷酸化WIPI2直接控制自噬体的形成，WIPI2是隔离膜生长和延伸的关键蛋白。mTORC 1磷酸化WIPI2的Ser395，指导WIPI2与E3泛素连接酶HUWE1特异性相互作用，用于泛素化和蛋白酶体降解。细胞中mTORC 1的生理学或药理学抑制促进WIPI2稳定化、自体吞噬体形成和自体吞噬降解。在小鼠肝脏中，禁食显著增加WIPI2蛋白水平，而沉默HUWE1增强自噬，引入WIPI2改善脂质清除。因此，mTORC 1和HUWE 1对细胞内WIPI2蛋白水平的调节是自噬通量的关键决定因素，并可能协调自噬的启动、进展和完成。
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, auto-phagosome 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.