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

• DOI: 10.1016/j.molcel.2020.12.008
• Publication Date: 2021-01-09T16:21:05Z
• Authors: Peng Jiang; Lejiao Ren; Li Zhi; Zhong Yu; Fengxiang Lv; Fengli Xu; Wei Peng; Xiaoyu Bai; Kunlun Cheng; Li Quan; Xiuqin Zhang; Xianhua Wang; Yan Zhang; Dan Yang; Xinli Hu; Rui-Ping Xiao
• Keywords: AMP-Activated Protein Kinase; Overnutrition

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.