Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is an important cellular metabolite-sensing enzyme that can directly sense changes not only in ATP but also in metabolites associated with carbohydrates and fatty acids. However, less is known about whether and how AMPK senses variations in cellular amino acids. Here, we show that cysteine deficiency significantly triggers calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-mediated activation of AMPK. In addition, we found that CaMKK2 directly associates with cysteinyl-tRNA synthetase (CARS), which then binds to AMPKγ2 under cysteine deficiency to activate AMPK. Interestingly, we discovered that cysteine inhibits the binding of CARS to AMPKγ2, and thus, under cysteine deficiency conditions wherein the inhibitory effect of cysteine is abrogated, CARS mediates the binding of AMPK to CaMKK2, resulting in the phosphorylation and activation of AMPK by CaMKK2. Importantly, we demonstrate that blocking AMPK activation leads to cell death under cysteine-deficient conditions. In summary, our study is the first to show that CARS senses the absence of cysteine and activates AMPK through the cysteine–CARS–CaMKK2–AMPKγ2 axis, a novel adaptation strategy for cell survival under nutrient deprivation conditions.

中文翻译：

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CARS 感知半胱氨酸剥夺以激活 AMPK 以促进细胞存活

腺苷 5'-一磷酸 (AMP) 活化蛋白激酶 (AMPK) 是一种重要的细胞代谢物传感酶，它不仅可以直接感知 ATP 的变化，还可以直接感知与碳水化合物和脂肪酸相关的代谢物的变化。然而，对于 AMPK 是否以及如何感知细胞氨基酸的变化知之甚少。在这里，我们表明半胱氨酸缺乏会显着触发钙/钙调蛋白依赖性蛋白激酶激酶 2 (CaMKK2) 介导的 AMPK 激活。此外，我们发现 CaMKK2 直接与半胱氨酰-tRNA 合成酶 (CARS) 结合，然后在半胱氨酸缺乏的情况下与 AMPKγ2 结合以激活 AMPK。有趣的是，我们发现半胱氨酸抑制CARS与AMPKγ2的结合，因此，在半胱氨酸缺乏条件下，其中半胱氨酸的抑制作用被消除，CARS 介导 AMPK 与 CaMKK2 的结合，导致 CaMKK2 磷酸化和激活 AMPK。重要的是，我们证明阻断 AMPK 活化会导致半胱氨酸缺乏条件下的细胞死亡。总之，我们的研究首次表明 CARS 感知半胱氨酸的缺失并通过半胱氨酸-CARS-CaMKK2-AMPKγ2 轴激活 AMPK，这是一种在营养剥夺条件下细胞存活的新适应策略。