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. Epub 2021 Jan 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / enzymology*
  • Diabetes Mellitus / genetics
  • Disease Models, Animal
  • Glucose / pharmacology*
  • HEK293 Cells
  • Humans
  • Macaca mulatta
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / enzymology
  • Obesity / blood
  • Obesity / enzymology*
  • Obesity / genetics
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Proteolysis
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Ubiquitination


  • Blood Glucose
  • MG53 protein, mouse
  • Membrane Proteins
  • Reactive Oxygen Species
  • AMPK alpha2 subunit, mouse
  • PRKAA2 protein, human
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • Stk11 protein, mouse
  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases
  • Glucose