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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mycobacterium tuberculosis WhiB3 responds to O_2 and nitric oxide via its [4Fe-4S] cluster and is essential for nutrient starvation survival
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Mycobacterium tuberculosis WhiB3 responds to O_2 and nitric oxide via its [4Fe-4S] cluster and is essential for nutrient starvation survival

机译：结核分枝杆菌WhiB3通过其[4Fe-4S]簇响应O_2和一氧化氮，对于营养饥饿的生存至关重要

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摘要

A fundamental challenge in the redox biology of Mycobacterium tuberculosis (Mtb) is to understand the mechanisms involved in sensing redox signals such as oxygen (O_2), nitric oxide (NO), and nutrient depletion, which are thought to play a crucial role in persistence. Here we show that Mtb WhiB3 responds to the dormancy signals NO and O_2 through its iron-sulfur (Fe-S) cluster. To functionally assemble the WhiB3 Fe-S cluster, we identified and characterized the Mtb cysteine desulfurase (IscS; Rv3025c) and developed a native enzymatic reconstitution system for assembling Fe-S clusters in Mtb. EPR and UV-visible spectroscopy analysis of reduced WhiB3 is consistent with a one-electron reduction of EPR silent [4Fe-4S]~(2+) to EPR visible [4Fe-4S]~+. Atmospheric O_2 gradually degrades the WhiB3 [4Fe-4S]~(2+) cluster to generate a [3Fe-4S]~+ intermediate. Furthermore, EPR analysis demonstrates that NO forms a protein-bound dinitrosyl-iron-dithiol complex with the Fe-S cluster, indicating that NO specifically targets the WhiB3 Fe-S cluster. Our data suggest that the mechanism of WhiB3 4Fe-4S cluster degradation is similar to that of fumarate nitrate regulator. Importantly, Mtb ΔwhiB3 shows enhanced growth on acetate medium, but a growth defect on media containing glucose, pyruvate, succinate, or fumarate as the sole carbon source. Our results implicate WhiB3 in metabolic switching and in sensing the physiologically relevant host signaling molecules NO and O_2 through its [4Fe-4S] cluster. Taken together, our results suggest that WhiB3 is an intracellular redox sensor that integrates environmental redox signals with core intermediary metabolism.
机译：结核分枝杆菌（Mtb）氧化还原生物学的一个基本挑战是要了解与感知氧化还原信号有关的机制，例如氧（O_2），一氧化氮（NO）和营养耗竭，它们在持久性中起着至关重要的作用。 。在这里，我们显示Mtb WhiB3通过其铁硫（Fe-S）簇响应休眠信号NO和O_2。为了功能性组装WhiB3 Fe-S簇，我们鉴定并鉴定了Mtb半胱氨酸脱硫酶（IscS; Rv3025c），并开发了用于在Mtb中组装Fe-S簇的天然酶重建系统。还原的WhiB3的EPR和紫外-可见光谱分析与EPR沉默[4Fe-4S]〜（2+）到EPR可见[4Fe-4S]〜+的单电子还原相符。大气O_2逐渐降解WhiB3 [4Fe-4S]〜（2+）团簇，生成[3Fe-4S]〜+中间体。此外，EPR分析表明，NO与Fe-S簇形成蛋白质结合的二亚硝酰基-铁-二硫醇复合物，表明NO专门针对WhiB3 Fe-S簇。我们的数据表明，WhiB3 4Fe-4S团簇降解的机理与富马酸盐硝酸盐调节剂相似。重要的是，MtbΔwhiB3在乙酸盐培养基上显示出增强的生长，但在包含葡萄糖，丙酮酸，琥珀酸盐或富马酸酯作为唯一碳源的培养基上显示出生长缺陷。我们的研究结果暗示WhiB3参与代谢转换，并通过其[4Fe-4S]簇感知生理相关的宿主信号分子NO和O_2。两者合计，我们的结果表明WhiB3是将环境氧化还原信号与核心中间代谢相结合的细胞内氧化还原传感器。

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