2. Academic Validation
  3. Negative regulation of AMPK signaling by high glucose via E3 ubiquitin ligase MG53

Negative regulation of AMPK signaling by high glucose via E3 ubiquitin ligase MG53

  • Mol Cell. 2021 Feb 4;81(3):629-637.e5. doi: 10.1016/j.molcel.2020.12.008.
Peng Jiang 1,  Lejiao Ren 2,  Li Zhi 2,  Zhong Yu 1,  Fengxiang Lv 1,  Fengli Xu 2,  Wei Peng 1,  Xiaoyu Bai 3,  Kunlun Cheng 1,  Li Quan 1,  Xiuqin Zhang 1,  Xianhua Wang 1,  Yan Zhang 1,  Dan Yang 3,  Xinli Hu 4,  Rui-Ping Xiao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
  • 2 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
  • 3 Morningside Laboratory for Chemical Biology, Department of Chemistry, The University of Hong Kong, Hong Kong, China.
  • 4 State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China; PKU-Nanjing Institute of Translational Medicine, Nanjing 211800, China. Electronic address: [email protected].
PMID: 33400924 DOI: 10.1016/j.molcel.2020.12.008
Abstract

As a master regulator of metabolism, AMP-activated protein kinase (AMPK) is activated upon energy and glucose shortage but suppressed upon overnutrition. Exaggerated negative regulation of AMPK signaling by nutrient overload plays a crucial role in metabolic diseases. However, the mechanism underlying the negative regulation is poorly understood. Here, we demonstrate that high glucose represses AMPK signaling via MG53 (also called TRIM72) E3-ubiquitin-ligase-mediated AMPKα degradation and deactivation. Specifically, high-glucose-stimulated Reactive Oxygen Species (ROS) signals Akt to phosphorylate AMPKα at S485/491, which facilitates the recruitment of MG53 and the subsequent ubiquitination and degradation of AMPKα. In addition, high glucose deactivates AMPK by ROS-dependent suppression of phosphorylation of AMPKα at T172. These findings not only delineate the mechanism underlying the impairment of AMPK signaling in overnutrition-related diseases but also highlight the significance of keeping the yin-yang balance of AMPK signaling in the maintenance of metabolic homeostasis.

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