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Chemoproteomic profiling reveals cellular targets of nitro-fatty acids
Redox Biology ( IF 10.7 ) Pub Date : 2021-09-07 , DOI: 10.1016/j.redox.2021.102126
Ming-Yu Fang , Kuan-Hsun Huang , Wei-Ju Tu , Yi-Ting Chen , Pei-Yun Pan , Wan-Chi Hsiao , Yi-Yu Ke , Lun K. Tsou , Mingzi M. Zhang

Nitro-fatty acids are a class of endogenous electrophilic lipid mediators with anti-inflammatory and cytoprotective effects in a wide range of inflammatory and fibrotic disease models. While these beneficial biological effects of nitro-fatty acids are mainly attributed to their ability to form covalent adducts with proteins, only a small number of proteins are known to be nitro-alkylated and the scope of protein nitro-alkylation remains undetermined. Here we describe the synthesis and application of a clickable nitro-fatty acid probe for the detection and first global identification of mammalian proteins that are susceptible to nitro-alkylation. 184 high confidence nitro-alkylated proteins were identified in THP1 macrophages, majority of which are novel targets of nitro-fatty acids, including extended synaptotagmin 2 (ESYT2), signal transducer and activator of transcription 3 (STAT3), toll-like receptor 2 (TLR2), retinoid X receptor alpha (RXRα) and glucocorticoid receptor (NR3C1). In particular, we showed that 9-nitro-oleate covalently modified and inhibited dexamethasone binding to NR3C1. Bioinformatic analyses revealed that nitro-alkylated proteins are highly enriched in endoplasmic reticulum and transmembrane proteins, and are overrepresented in lipid metabolism and transport pathways. This study significantly expands the scope of protein substrates targeted by nitro-fatty acids in living cells and provides a useful resource towards understanding the pleiotropic biological roles of nitro-fatty acids as signaling molecules or as multi-target therapeutic agents.



中文翻译:

化学蛋白质组学分析揭示硝基脂肪酸的细胞靶点

硝基脂肪酸是一类内源性亲电脂质介质,在广泛的炎症和纤维化疾病模型中具有抗炎和细胞保护作用。虽然硝基脂肪酸的这些有益生物效应主要归因于它们与蛋白质形成共价加合物的能力,但只有少数蛋白质被硝基烷基化,蛋白质硝基烷基化的范围仍未确定。在这里,我们描述了可点击的硝基脂肪酸探针的合成和应用,用于检测和首次全球鉴定对硝基烷基化敏感的哺乳动物蛋白质。在 THP1 巨噬细胞中鉴定了 184 种高可信度的硝基烷基化蛋白,其中大部分是硝基脂肪酸的新靶点,包括扩展突触结合蛋白 2 (ESYT2),信号转导和转录激活因子 3 (STAT3)、toll 样受体 2 (TLR2)、类视黄醇 X 受体α (RXRα) 和糖皮质激素受体 (NR3C1)。特别是,我们发现 9-硝基油酸酯共价修饰并抑制地塞米松与 NR3C1 的结合。生物信息学分析表明,硝基烷基化蛋白在内质网和跨膜蛋白中高度富集,在脂质代谢和转运途径中含量过高。这项研究显着扩大了活细胞中硝基脂肪酸靶向蛋白质底物的范围,并为了解硝基脂肪酸作为信号分子或多靶点治疗剂的多效生物学作用提供了有用的资源。类视黄醇 X 受体α (RXRα) 和糖皮质激素受体 (NR3C1)。特别是,我们发现 9-硝基油酸酯共价修饰并抑制地塞米松与 NR3C1 的结合。生物信息学分析表明,硝基烷基化蛋白在内质网和跨膜蛋白中高度富集,在脂质代谢和转运途径中含量过高。这项研究显着扩大了活细胞中硝基脂肪酸靶向蛋白质底物的范围,并为了解硝基脂肪酸作为信号分子或多靶点治疗剂的多效生物学作用提供了有用的资源。类视黄醇 X 受体α (RXRα) 和糖皮质激素受体 (NR3C1)。特别是,我们发现 9-硝基油酸酯共价修饰并抑制地塞米松与 NR3C1 的结合。生物信息学分析表明,硝基烷基化蛋白在内质网和跨膜蛋白中高度富集,在脂质代谢和转运途径中含量过高。这项研究显着扩大了活细胞中硝基脂肪酸靶向蛋白质底物的范围,并为了解硝基脂肪酸作为信号分子或多靶点治疗剂的多效生物学作用提供了有用的资源。生物信息学分析表明,硝基烷基化蛋白在内质网和跨膜蛋白中高度富集,在脂质代谢和转运途径中含量过高。这项研究显着扩大了活细胞中硝基脂肪酸靶向蛋白质底物的范围,并为了解硝基脂肪酸作为信号分子或多靶点治疗剂的多效生物学作用提供了有用的资源。生物信息学分析表明,硝基烷基化蛋白在内质网和跨膜蛋白中高度富集,在脂质代谢和转运途径中含量过高。这项研究显着扩大了活细胞中硝基脂肪酸靶向蛋白质底物的范围,并为了解硝基脂肪酸作为信号分子或多靶点治疗剂的多效生物学作用提供了有用的资源。

更新日期:2021-09-10
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