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
  • 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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