例如:"lncRNA", "apoptosis", "WRKY"

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

Mol Cell. 2018 Oct 18;72(2):303-315.e6
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
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
+ et al

[No authors listed]

Author information
  • 1 Department of Biochemistry and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 2 National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 3 Department of Biochemistry and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address: liuwei666@zju.edu.cn.

摘要


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.

KEYWORDS: HUWE1, WIPI2, autophagy, mTORC1, ubiquitination