厦门大学林圣彩、张宸崧课题组报道了AMPK靶向PDZD8，触发碳源从葡萄糖向谷氨酰胺的转变。2024年6月19日出版的《细胞研究》杂志发表了这项成果。

该团队发现含有8的PDZ结构域(PDZD8)是低糖激活的AMPK的新底物，是低糖促进谷氨酰胺水解所必需的。AMPK磷酸化PDZD8的苏氨酸527 (T527)，促进PDZD8与谷氨酰胺酶1 (GLS1)的相互作用和激活，GLS1是谷氨酰胺水解的限速酶。在体内，在骨骼肌组织中，AMPK-PDZD8-GLS1轴是谷氨酰胺溶解增强所必需的，其发生时间早于禁食期间脂肪酸利用的增加。

在低糖或急性脂多糖(LPS)处理下，巨噬细胞也观察到增强的谷氨酰胺水解。PDZD8-T527A突变抑制LPS处理小鼠巨噬细胞中促炎细胞因子的分泌，这与谷氨酰胺水解升高的需求一致。课题组研究人员共同发现了AMPK-PDZD8-GLS1轴，在葡萄糖短缺的情况下，在脂肪酸利用增加之前促进谷氨酰胺水解。

据介绍，从主要葡萄糖到其他营养物质碳利用的转变是一种基本的代谢适应，以应对血糖水平下降和随之而来的葡萄糖氧化下降。AMP活化蛋白激酶(AMPK)在这种代谢适应中起着至关重要的作用。然而，其潜在的机制尚不完全清楚。

附：英文原文

Title: AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine

Author: Li, Mengqi, Wang, Yu, Wei, Xiaoyan, Cai, Wei-Feng, Wu, Jianfeng, Zhu, Mingxia, Wang, Yongliang, Liu, Yan-Hui, Xiong, Jinye, Qu, Qi, Chen, Yan, Tian, Xiao, Yao, Luming, Xie, Renxiang, Li, Xiaomin, Chen, Siwei, Huang, Xi, Zhang, Cixiong, Xie, Changchuan, Wu, Yaying, Xu, Zheni, Zhang, Baoding, Jiang, Bin, Wang, Zhi-Chao, Li, Qinxi, Li, Gang, Lin, Shu-Yong, Yu, Li, Piao, Hai-Long, Deng, Xianming, Han, Jiahuai, Zhang, Chen-Song, Lin, Sheng-Cai

Issue&Volume: 2024-06-19

Abstract: The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.

DOI: 10.1038/s41422-024-00985-6

Source: https://www.nature.com/articles/s41422-024-00985-6