Quorum-Sensing Signaling Molecule 2-Aminoacetophenone Mediates the Persistence of Pseudomonas aeruginosa in Macrophages by Interference with Autophagy through Epigenetic Regulation of Lipid Biosynthesis.
Quorum-Sensing Signaling Molecule 2-Aminoacetophenone Mediates the Persistence of Pseudomonas aeruginosa in Macrophages by Interference with Autophagy through Epigenetic Regulation of Lipid Biosynthesis.
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巨噬细胞是宿主防御病原体的重要组成部分。最近的研究表明巨噬细胞的功能受到脂质代谢的影响。然而，关于细菌病原体如何利用巨噬细胞脂质代谢来发挥其作用的知识仍然很初级。我们已经证明，铜绿假单胞菌 MvfR 调节的群体感应 (QS) 信号分子 2-氨基苯乙酮 (2-AA) 介导与该病原体在体内持续存在相关的表观遗传和代谢变化。我们提供的证据表明，2-AA 会抵消巨噬细胞清除细胞内铜绿假单胞菌的能力，从而导致其持续存在。巨噬细胞中 2-AA 的细胞内作用与自噬功能降低和中心脂肪生成基因硬脂酰辅酶 A 去饱和酶 1 (Scd1) 的表达受损有关，该基因催化单不饱和脂肪酸的生物合成。 2-AA 还可降低自噬基因 Unc-51 样自噬激活激酶 1 (ULK1) 和 Beclin1 的表达，以及自噬体膜蛋白微管相关蛋白 1、轻链 3 同工型 B (LC3B) 和 p62 的水平。自噬减少伴随着脂肪生成基因 Scd1 表达的减少，从而阻止细菌清除。添加 SCD1 底物棕榈酰辅酶 A 和硬脂酰辅酶 A 可增加巨噬细胞对铜绿假单胞菌的清除率。 2-AA 对脂肪生成基因表达和自噬机制的影响是由组蛋白脱乙酰酶 1 (HDAC1) 介导的，这表明 Scd1 和 Beclin1 基因启动子位点上有 HDAC1 表观遗传标记。这项工作为 QS 促进的复杂代谢改变和表观遗传调控提供了新的见解，并揭示了支持巨噬细胞中铜绿假单胞菌维持的其他 2-AA 作用。这些发现可能有助于设计针对铜绿假单胞菌持久性的针对宿主的治疗方法和保护性干预措施。
Macrophages are crucial components of the host’s defense against pathogens. Recent studies indicate that macrophage functions are influenced by lipid metabolism. However, knowledge of how bacterial pathogens exploit macrophage lipid metabolism for their benefit remains rudimentary. We have shown that the Pseudomonas aeruginosa MvfR-regulated quorum-sensing (QS) signaling molecule 2-aminoacetophenone (2-AA) mediates epigenetic and metabolic changes associated with this pathogen’s persistence in vivo. We provide evidence that 2-AA counteracts the ability of macrophages to clear the intracellular P. aeruginosa, leading to persistence. The intracellular action of 2-AA in macrophages is linked to reduced autophagic functions and the impaired expression of a central lipogenic gene, stearoyl-CoA desaturase 1 (Scd1), which catalyzes the biosynthesis of monounsaturated fatty acids. 2-AA also reduces the expression of the autophagic genes Unc-51-like autophagy activating kinase 1 (ULK1) and Beclin1 and the levels of the autophagosomal membrane protein microtubule-associated protein 1, light chain 3 isoform B (LC3B) and p62. Reduced autophagy is accompanied by the reduced expression of the lipogenic gene Scd1, preventing bacterial clearance. Adding the SCD1 substrates palmitoyl-CoA and stearoyl-CoA increases P. aeruginosa clearance by macrophages. The impact of 2-AA on lipogenic gene expression and autophagic machinery is histone deacetylase 1 (HDAC1) mediated, implicating the HDAC1 epigenetic marks at the promoter sites of Scd1 and Beclin1 genes. This work provides novel insights into the complex metabolic alterations and epigenetic regulation promoted by QS and uncovers additional 2-AA actions supporting P. aeruginosa sustainment in macrophages. These findings may aid in designing host-directed therapeutics and protective interventions against P. aeruginosa persistence.
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影响因子：
--
作者：
Dulcey CE;Dekimpe V;Fauvelle DA;Milot S;Groleau MC;Doucet N;Rahme LG;Lépine F;Déziel E
通讯作者：
Déziel E
法定感应的挥发性分子2-氨基乙烯酮以促进不必要的客人生活的方式调节宿主免疫反应。
影响因子：
6.7
作者：
Bandyopadhaya A;Kesarwani M;Que YA;He J;Padfield K;Tompkins R;Rahme LG
通讯作者：
Rahme LG
影响因子：
4.4
作者：
Kannan, Shibichakravarthy;Audet, Aaron;Wu, Min
通讯作者：
Wu, Min
影响因子：
6.7
作者：
Anderson, Sarah M.;Cheesman, Hilary K.;Pukkila-Worley, Read
通讯作者：
Pukkila-Worley, Read
DOI：
10.1073/pnas.251465298
发表时间：
2001-12-04
影响因子：
11.1
作者：
Cao, H;Krishnan, G;Rahme, LG
通讯作者：
Rahme, LG