Amino acid metabolites that regulate G protein signaling during osmotic stress.
Amino acid metabolites that regulate G protein signaling during osmotic stress.
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DOI：
10.1371/journal.pgen.1006829
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发表时间：
2017-05
期刊：
影响因子：
4.5
通讯作者：
Dohlman HG
中科院分区：
文献类型：
--
作者：
Shellhammer JP;Morin-Kensicki E;Matson JP;Yin G;Isom DG;Campbell SL;Mohney RP;Dohlman HG
所有细胞对渗透胁迫作出反应，通过实施分子信号事件来保护生物体。不能适当地适应可导致高血压和缺血再灌注损伤等病理。有丝分裂原活化蛋白激酶（MAPKs）在渗透胁迫下被激活，也通过G蛋白偶联受体（gpcr）的信号被激活。为了适当的适应，这些激酶的作用必须协调一致。为了确定胁迫适应的第二信使，我们进行了基于质谱的全球代谢组学分析，量化了酵母S. cerevisiae中的近300种代谢物。我们发现，三种支链氨基酸（BCAA）代谢物在渗透胁迫下增加，需要MAPK Hog1。这些BCAA衍生物的异位添加促进G蛋白α亚基的磷酸化，并抑制G蛋白依赖的转录，类似于对渗透胁迫的反应。相反，Hog1活性或bcaa调节酶的基因消融会导致Gα磷酸化减少和转录增加。综上所述，我们的研究结果定义了一类新的候选第二信使，它们介导渗透胁迫和GPCR信号通路之间的串扰。就像生物体必须适应具有挑战性的环境一样，细胞必须对生物体内部发生的化学或物理变化做出反应。不管环境因素如何，所有细胞都使用分子信号通路对这些变化做出反应。许多是通过G蛋白偶联受体（gpcr）或高渗透压甘油（HOG）途径传递的。虽然这些途径已经独立研究了几十年，但人们对它们如何相互协调以进行适当的反应知之甚少，特别是当存在相互冲突的信号时。实现协调的一种方式是通过一种途径产生的“第二信使”分子来调节另一种途径。在这里，我们通过对酿酒酵母的全球代谢物分析，确定了渗透胁迫的候选第二信使。我们发现三种支链氨基酸（BCAA）代谢物在渗透胁迫下增加，并需要胁迫响应MAPK Hog1。我们表明，这些BCAA衍生物是必要的，足以概括渗透胁迫对GPCR途径的影响。我们的研究结果确定了HOG和GPCR途径沟通的新途径，并可能在未来指导更好的治疗应激相关细胞损伤的策略。
All cells respond to osmotic stress by implementing molecular signaling events to protect the organism. Failure to properly adapt can lead to pathologies such as hypertension and ischemia-reperfusion injury. Mitogen-activated protein kinases (MAPKs) are activated in response to osmotic stress, as well as by signals acting through G protein-coupled receptors (GPCRs). For proper adaptation, the action of these kinases must be coordinated. To identify second messengers of stress adaptation, we conducted a mass spectrometry-based global metabolomics profiling analysis, quantifying nearly 300 metabolites in the yeast S. cerevisiae. We show that three branched-chain amino acid (BCAA) metabolites increase in response to osmotic stress and require the MAPK Hog1. Ectopic addition of these BCAA derivatives promotes phosphorylation of the G protein α subunit and dampens G protein-dependent transcription, similar to that seen in response to osmotic stress. Conversely, genetic ablation of Hog1 activity or the BCAA-regulatory enzymes leads to diminished phosphorylation of Gα and increased transcription. Taken together, our results define a new class of candidate second messengers that mediate cross talk between osmotic stress and GPCR signaling pathways. Just as organisms must adapt to a challenging environment, cells must respond to chemical or physical changes that occur within the organism. Regardless of the environmental cue, all cells use molecular signaling pathways to respond to those changes. Many are transmitted by G protein-coupled receptors (GPCRs) or the high osmolarity glycerol (HOG) pathway. While these pathways have been studied independently for decades, less is known about how they coordinate with each other to carry out the proper response, particularly when conflicting signals are present. One way coordination can be achieved is through “second messenger” molecules produced by one pathway to regulate another pathway. Here, we identify candidate second messengers of osmotic stress by global metabolite profiling analysis of the yeast S. cerevisiae. We find that three branched-chain amino acid (BCAA) metabolites increase in response to osmotic stress and require the stress response MAPK Hog1. We show that these BCAA derivatives are necessary and sufficient to recapitulate the effects of osmotic stress on the GPCR pathway. Our results identify a new way that HOG and GPCR pathways communicate, and may in the future guide better treatment strategies for stress-related cell damage.