Intracellular Zn(II) Intoxication Leads to Dysregulation of the PerR Regulon Resulting in Heme Toxicity in Bacillus subtilis.
Intracellular Zn(II) Intoxication Leads to Dysregulation of the PerR Regulon Resulting in Heme Toxicity in Bacillus subtilis.
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DOI：
10.1371/journal.pgen.1006515
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发表时间：
2016-12
期刊：
影响因子：
4.5
通讯作者：
Helmann JD
中科院分区：
文献类型：
--
作者：
Chandrangsu P;Helmann JD
过渡金属离子（Zn（II）、Cu（II）/（I）、Fe（III）/（II）、Mn（II））是生命所必需的，并参与广泛的生物功能。细胞中的锌（II）水平必须足够高，以确保它能够发挥其重要作用。然而，由于Zn（II）与具有高亲合力的配体结合，过量的Zn（II）可导致蛋白质错配。错代谢的主要目标，以及锌（II）中毒的根本原因，还没有很好地理解。在这里，我们使用正向遗传选择，以确定锌（II）毒性的目标。在野生型细胞，其中锌（II）流出防止中毒的细胞质，胞外锌（II）抑制电子传递链由于失活的主要需氧细胞色素氧化酶。这种毒性可以通过抑制替代氧化酶或通过限制Zn（II）进入细胞表面的突变来改善。相反，外排缺陷细胞对不抑制呼吸链的低水平Zn（II）敏感。在这些条件下，细胞内Zn（II）积累并导致血红素毒性。血红素积累的结果由PerR，一种金属依赖性抑制剂的过氧化物应激基因控制的调节子失调。当与Fe（II）或Mn（II）金属化时，PerR抑制血红素生物合成（hemAXCDBL操纵子）和丰富的血红素蛋白过氧化氢酶（katA）。代谢的PerR与锌（II）破坏这种协调，导致血红素生物合成的抑郁症，但继续抑制过氧化氢酶。我们的研究结果支持一个模型，其中过量的血红素分区的膜，并经历氧化还原循环催化还原甲基萘醌，从而导致氧化应激。锌（Zn（II））通常被认为是金属离子体内平衡中的“第一个”。锌（II）对许多细胞过程的正常功能至关重要，但在高水平下是有毒的。锌（II）中毒的分子基础知之甚少。在B中使用正向遗传方法。枯草杆菌，我们表明，外部Zn（II）的水平升高抑制电子传递链，而细胞内Zn（II）中毒是由于血红素生物合成失调。由于宿主免疫系统利用锌（II）螯合和毒性作为应对病原体的一种手段，这些发现有助于我们理解宿主-微生物相互作用。
Transition metal ions (Zn(II), Cu(II)/(I), Fe(III)/(II), Mn(II)) are essential for life and participate in a wide range of biological functions. Cellular Zn(II) levels must be high enough to ensure that it can perform its essential roles. Yet, since Zn(II) binds to ligands with high avidity, excess Zn(II) can lead to protein mismetallation. The major targets of mismetallation, and the underlying causes of Zn(II) intoxication, are not well understood. Here, we use a forward genetic selection to identify targets of Zn(II) toxicity. In wild-type cells, in which Zn(II) efflux prevents intoxication of the cytoplasm, extracellular Zn(II) inhibits the electron transport chain due to the inactivation of the major aerobic cytochrome oxidase. This toxicity can be ameliorated by depression of an alternate oxidase or by mutations that restrict access of Zn(II) to the cell surface. Conversely, efflux deficient cells are sensitive to low levels of Zn(II) that do not inhibit the respiratory chain. Under these conditions, intracellular Zn(II) accumulates and leads to heme toxicity. Heme accumulation results from dysregulation of the regulon controlled by PerR, a metal-dependent repressor of peroxide stress genes. When metallated with Fe(II) or Mn(II), PerR represses both heme biosynthesis (hemAXCDBL operon) and the abundant heme protein catalase (katA). Metallation of PerR with Zn(II) disrupts this coordination, resulting in depression of heme biosynthesis but continued repression of catalase. Our results support a model in which excess heme partitions to the membrane and undergoes redox cycling catalyzed by reduced menaquinone thereby resulting in oxidative stress. Zinc (Zn(II)) is often considered to be a “first among equals” in metal ion homeostasis. Zn(II) is critically important to the proper function of many cellular processes, yet is toxic at high levels. The molecular basis for Zn(II) intoxication is poorly understood. Using a forward genetic approach in B. subtilis, we demonstrate that elevated levels of external Zn(II) inhibit the electron transport chain, whereas intracellular Zn(II) intoxication is due to dysregulation of heme biosynthesis. Since the host immune system utilizes both Zn(II) sequestration and toxicity as a means of responding to pathogens, these findings contribute to our understanding of host-microbe interactions.
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