Staphylococcus aureus redirects central metabolism to increase iron availability.
Staphylococcus aureus redirects central metabolism to increase iron availability.
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DOI：
10.1371/journal.ppat.0020087
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发表时间：
2006-08
期刊：
影响因子：
6.7
通讯作者：
Skaar EP
中科院分区：
文献类型：
--
作者：
Friedman DB;Stauff DL;Pishchany G;Whitwell CW;Torres VJ;Skaar EP
金黄色葡萄球菌的发病机制受宿主铁状况的显著影响。然而，宿主铁源对S. aureus基因表达仍然未知。在这项研究中，我们结合联合收割机多变量差异凝胶电泳和质谱与多变量统计分析，系统聚类细胞蛋白质反应在不同的铁暴露条件。同时分析四倍体样品中蛋白丰度和/或翻译后修饰状态的变化，以响应细菌铁暴露中的环境（铁螯合、氯化血红素处理）或遗传（Δfur）变化。我们确定了120种蛋白质，代表了几种受铁暴露状态变化影响的协调生化途径。在这些实验中突出的是血红素调节的运输系统（HrtAB），一种新的运输系统，在葡萄球菌血红素代谢中起着关键作用的识别。此外，我们表明，受管制的过量生产的酸性终产物所带来的铁饥饿降低当地pH值，导致从主机铁螯合蛋白转铁蛋白释放铁。这些发现揭示了S.金黄色葡萄球菌在恶劣的宿主环境中获得稀缺的营养物质，并开始定义铁和血红素依赖的调节子。金黄色。几乎所有的细菌病原体都需要铁才能成功感染人类宿主。这给入侵的细菌带来了一个问题，因为人体内的大部分铁都被铁结合蛋白紧密结合。为了对抗这种宿主防御，细菌病原体已经开发出复杂的机制来在感染期间获得营养铁。为了深入了解可用铁的量如何影响人类病原体金黄色葡萄球菌，作者确定了在铁状态改变时增加或减少丰度的蛋白质。作者发现，在铁饥饿条件下，S.金黄色葡萄球菌协调中心代谢途径的重定向，导致细菌产生大量酸性终产物。这些酸性终产物的积累促进了铁从宿主铁结合蛋白中的释放，实际上增加了这种珍贵营养源的可用性。这些发现为S.金黄色葡萄球菌在感染期间改变其局部微环境以增加营养铁的可用性。基于致病过程中细菌铁获取的既定作用，涉及铁获取的系统代表了针对细菌感染的极好的潜在治疗靶点。
Staphylococcus aureus pathogenesis is significantly influenced by the iron status of the host. However, the regulatory impact of host iron sources on S. aureus gene expression remains unknown. In this study, we combine multivariable difference gel electrophoresis and mass spectrometry with multivariate statistical analyses to systematically cluster cellular protein response across distinct iron-exposure conditions. Quadruplicate samples were simultaneously analyzed for alterations in protein abundance and/or post-translational modification state in response to environmental (iron chelation, hemin treatment) or genetic (Δfur) alterations in bacterial iron exposure. We identified 120 proteins representing several coordinated biochemical pathways that are affected by changes in iron-exposure status. Highlighted in these experiments is the identification of the heme-regulated transport system (HrtAB), a novel transport system which plays a critical role in staphylococcal heme metabolism. Further, we show that regulated overproduction of acidic end-products brought on by iron starvation decreases local pH resulting in the release of iron from the host iron-sequestering protein transferrin. These findings reveal novel strategies used by S. aureus to acquire scarce nutrients in the hostile host environment and begin to define the iron and heme-dependent regulons of S. aureus. Virtually all bacterial pathogens require iron to successfully infect their human hosts. This presents a problem to invading bacteria because the majority of iron in humans is tightly bound by iron-binding proteins. To counteract this host defense, bacterial pathogens have developed elaborate mechanisms to acquire nutrient iron during infection. To gain insight into how the amount of available iron impacts the human pathogen Staphylococcus aureus, the authors identified proteins that increase or decrease abundance upon alterations in iron status. The authors found that under conditions of iron starvation, the Fur regulatory protein of S. aureus coordinates a redirection of the central metabolic pathways causing the bacteria to produce large amounts of acidic end-products. The accumulation of these acidic end-products facilitates the release of iron from host iron-binding proteins, in effect increasing the availability of this precious nutrient source. These findings provide a mechanistic explanation for how S. aureus alters its local microenvironment during infection to increase the availability of nutrient iron. Based on the well-established role for bacterial iron acquisition during pathogenesis, systems involved in iron acquisition represent excellent potential therapeutic targets against bacterial infection.