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
复制标题
高葡萄糖通过 E3 泛素连接酶 MG53 对 AMPK 信号传导进行负调节。
DOI：
10.1016/j.molcel.2020.12.008
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发表时间：
2021-02-04
期刊：
影响因子：
16
通讯作者：
Xiao, Rui-Ping
中科院分区：
文献类型：
--
作者：
Jiang, Peng;Ren, Lejiao;Xiao, Rui-Ping
AMP激活的蛋白激酶(AMPK)作为代谢的主要调节因子，在能量和葡萄糖缺乏时被激活，而在营养过剩时被抑制。营养过载对AMPK信号的过度负调控在代谢性疾病中起着至关重要的作用。然而，人们对负面监管背后的机制知之甚少。在这里，我们证明了高糖通过MG53(也称为TRIM72)E3-泛素连接酶介导的AMPKα降解和失活来抑制AMPK信号。具体地说，高糖刺激的活性氧物种(ROS)在S485/491处向AKT发出信号，使AMPKα磷酸化，从而促进MG53的募集以及随后AMPKα的泛素化和降解。此外，高糖通过依赖ROS抑制T172处AMPKα的磷酸化来使AMPK失活。这些发现不仅阐明了AMPK信号在过度营养相关疾病中受损的机制，而且强调了保持AMPK信号的阴阳平衡在维持代谢动态平衡中的重要性。
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 AMPK alpha degradation and deactivation. Specifically, high-glucose-stimulated reactive oxygen species (ROS) signals AKT to phosphorylate AMPK alpha at S485/491, which facilitates the recruitment of MG53 and the subsequent ubiquitination and degradation of AMPK alpha. In addition, high glucose deactivates AMPK by ROS-dependent suppression of phosphorylation of AMPK alpha at T172. These findings not only delineate the mechanism underlying the impairment of AMPK signaling in over nutrition-related diseases but also highlight the significance of keeping the yin-yang balance of AMPK signaling in the maintenance of metabolic homeostasis.