Department of Biochemistry and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Mol Cell. 2018 Oct 18;72(2):303-315.e6. doi: 10.1016/j.molcel.2018.09.017.
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.
mTORC1 作为主要的稳态传感器和响应物，主要通过靶向自噬来调节细胞分解代谢。在这里，我们表明 mTORC1 通过磷酸化 WIPI2 直接控制自噬体的形成，WIPI2 是隔离膜生长和伸长的关键蛋白。mTORC1 磷酸化 WIPI2 的 Ser395，指导 WIPI2 与 E3 泛素连接酶 HUWE1 特异性相互作用，进行泛素化和蛋白酶体降解。在细胞中，生理或药理学抑制 mTORC1 会促进 WIPI2 的稳定、自噬体的形成和自噬的降解。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 则改善脂质清除。因此，mTORC1 和 HUWE1 对细胞内 WIPI2 蛋白水平的调节是自噬通量的关键决定因素，可能协调自噬的起始、进展和完成。
