HrrSA orchestrates a systemic response to heme and determines prioritization of terminal cytochrome oxidase expression
HrrSA orchestrates a systemic response to heme and determines prioritization of terminal cytochrome oxidase expression
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DOI：
10.1093/nar/gkaa415
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发表时间：
2020-05
影响因子：
14.9
通讯作者：
M. Keppel;Max Hünnefeld;Andrei Filipchyk;Ulrike Viets;Cedric-Farhad Davoudi;Aileen Krüger;C. Mack;E. Pfeifer;T. Polen;M. Baumgart;M. Bott;Julia Frunzke
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文献类型：
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作者：
M. Keppel;Max Hünnefeld;Andrei Filipchyk;Ulrike Viets;Cedric-Farhad Davoudi;Aileen Krüger;C. Mack;E. Pfeifer;T. Polen;M. Baumgart;M. Bott;Julia Frunzke
摘要血红素是一种多面性分子。虽然作为许多重要蛋白质的辅基，但升高的水平对细胞有毒。这种刺激的复杂性塑造了细菌网络的进化。然而，迄今为止，仅描述了少量由血红素响应调节剂控制的靶点。在这里，我们进行了染色质亲和纯化和测序，以提供全基因组的见解在体内启动子占用HrrA，反应调节剂的血红素调节的双组分系统HrrSA的谷氨酸棒杆菌。时间分辨分析揭示了HrrA与200多种不同的基因组靶点的动态结合，这些靶点编码与血红素生物合成、呼吸链、氧化应激反应和细胞包膜重塑相关的蛋白质。通过抑制胞质外功能σ因子sigC（其激活cydABCD操纵子），HrrA优先表达编码细胞色素bc 1-aa 3超复合物的基因。这也反映在ΔhrrA突变体中细胞色素aa 3氧化酶的活性显著降低。此外，我们的数据表明，HrrA还整合了血红素诱导的氧化应激反应，通过激活katA编码的过氧化氢酶。这些数据提供了系统策略的详细见解，细菌已经进化到对多功能信号分子血红素做出反应。
Abstract Heme is a multifaceted molecule. While serving as a prosthetic group for many important proteins, elevated levels are toxic to cells. The complexity of this stimulus has shaped bacterial network evolution. However, only a small number of targets controlled by heme-responsive regulators have been described to date. Here, we performed chromatin affinity purification and sequencing to provide genome-wide insights into in vivo promoter occupancy of HrrA, the response regulator of the heme-regulated two-component system HrrSA of Corynebacterium glutamicum. Time-resolved profiling revealed dynamic binding of HrrA to more than 200 different genomic targets encoding proteins associated with heme biosynthesis, the respiratory chain, oxidative stress response and cell envelope remodeling. By repression of the extracytoplasmic function sigma factor sigC, which activates the cydABCD operon, HrrA prioritizes the expression of genes encoding the cytochrome bc1-aa3 supercomplex. This is also reflected by a significantly decreased activity of the cytochrome aa3 oxidase in the ΔhrrA mutant. Furthermore, our data reveal that HrrA also integrates the response to heme-induced oxidative stress by activating katA encoding the catalase. These data provide detailed insights in the systemic strategy that bacteria have evolved to respond to the versatile signaling molecule heme.