1. mTORC1-Regulated and HUWE1-Mediated WIPI2 Degradation Controls Autophagy Flux.
- Author
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Wan, Wei, You, Zhiyuan, Zhou, Li, Xu, Yinfeng, Peng, Chao, Zhou, Tianhua, Yi, Cong, Shi, Yin, and Liu, Wei
- Subjects
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MTOR protein , *AUTOPHAGY , *PHOSPHORYLATION , *UBIQUITIN ligases , *GENE targeting - Abstract
Summary 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. Graphical Abstract Highlights • HUWE1 mediates the ubiquitination and degradation of WIPI2 • mTORC1 promotes WIPI2 degradation by phosphorylating WIPI2 • Phosphorylation at Ser395 of WIPI2 enhances HUWE1 interaction • WIPI2 level determines autophagy flux and lipid clearance Wan et al. report a direct involvement of mTORC1 in the control of phagophore growth. mTORC1-dependent phosphorylation directs WIPI2 to interact with its E3 ubiquitin ligase HUWE1, which leads to WIPI2 degradation and autophagy inhibition. This WIPI2 quantity control pathway is a key determinant of constitutive and adaptive autophagy. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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