Ullevig Sarah L, Kim Hong Seok, Short John D, Tavakoli Sina, Weintraub Susan T, Downs Kevin, Asmis Reto
1 Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio , San Antonio, Texas.
2 Department of Molecular Medicine, College of Medicine, Inha University , Incheon, Korea.
Antioxid Redox Signal. 2016 Nov 20;25(15):836-851. doi: 10.1089/ars.2015.6531. Epub 2016 May 17.
Protein S-glutathionylation, the formation of a mixed disulfide between glutathione and protein thiols, is an oxidative modification that has emerged as a new signaling paradigm, potentially linking oxidative stress to chronic inflammation associated with heart disease, diabetes, cancer, lung disease, and aging. Using a novel, highly sensitive, and selective proteomic approach to identify S-glutathionylated proteins, we tested the hypothesis that monocytes and macrophages sense changes in their microenvironment and respond to metabolic stress by altering their protein thiol S-glutathionylation status.
We identified over 130 S-glutathionylated proteins, which were associated with a variety of cellular functions, including metabolism, transcription and translation, protein folding, free radical scavenging, cell motility, and cell death. Over 90% of S-glutathionylated proteins identified in metabolically stressed THP-1 monocytes were also found in hydrogen peroxide (HO)-treated cells, suggesting that HO mediates metabolic stress-induced protein S-glutathionylation in monocytes and macrophages. We validated our findings in mouse peritoneal macrophages isolated from both healthy and dyslipidemic atherosclerotic mice and found that 52% of the S-glutathionylated proteins found in THP-1 monocytes were also identified in vivo. Changes in macrophage protein S-glutathionylation induced by dyslipidemia were sexually dimorphic.
We provide a novel mechanistic link between metabolic (and thiol oxidative) stress, macrophage dysfunction, and chronic inflammatory diseases associated with metabolic disorders.
Our data support the concept that changes in the extracellular metabolic microenvironment induce S-glutathionylation of proteins central to macrophage metabolism and a wide array of cellular signaling pathways and functions, which in turn initiate and promote functional and phenotypic changes in macrophages. Antioxid. Redox Signal. 25, 836-851.
蛋白质S-谷胱甘肽化，即谷胱甘肽与蛋白质硫醇之间形成混合二硫键，是一种氧化修饰，已成为一种新的信号传导模式，可能将氧化应激与与心脏病、糖尿病、癌症、肺病和衰老相关的慢性炎症联系起来。我们使用一种新颖、高度灵敏且具有选择性的蛋白质组学方法来鉴定S-谷胱甘肽化蛋白质，测试了单核细胞和巨噬细胞感知其微环境变化并通过改变其蛋白质硫醇S-谷胱甘肽化状态来应对代谢应激这一假说。
我们鉴定出130多种S-谷胱甘肽化蛋白质，它们与多种细胞功能相关，包括代谢、转录和翻译、蛋白质折叠、自由基清除、细胞运动和细胞死亡。在代谢应激的THP-1单核细胞中鉴定出的S-谷胱甘肽化蛋白质中，超过90%也在过氧化氢（H₂O₂）处理的细胞中被发现，这表明H₂O₂介导单核细胞和巨噬细胞中代谢应激诱导的蛋白质S-谷胱甘肽化。我们在从健康和血脂异常的动脉粥样硬化小鼠中分离出的小鼠腹膜巨噬细胞中验证了我们的发现，发现THP-1单核细胞中发现的52%的S-谷胱甘肽化蛋白质在体内也被鉴定出来。血脂异常诱导的巨噬细胞蛋白质S-谷胱甘肽化变化具有性别差异。
我们提供了代谢（和硫醇氧化）应激、巨噬细胞功能障碍以及与代谢紊乱相关的慢性炎症疾病之间的一种新颖的机制联系。
我们的数据支持这样一种概念，即细胞外代谢微环境的变化会诱导巨噬细胞代谢核心蛋白质以及广泛的细胞信号通路和功能的S-谷胱甘肽化，进而引发并促进巨噬细胞的功能和表型变化。《抗氧化与氧化还原信号》25, 836 - 851。
