Feedback inhibition in the PhoQ/PhoP signaling system by a membrane peptide.
Feedback inhibition in the PhoQ/PhoP signaling system by a membrane peptide.
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DOI：
10.1371/journal.pgen.1000788
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发表时间：
2009-12
期刊：
影响因子：
4.5
通讯作者：
Goulian M
中科院分区：
文献类型：
--
作者：
Lippa AM;Goulian M
PhoQ/PhoP信号系统响应于低镁和某些阳离子抗菌肽的存在。它调节在这些条件下对生长重要的基因，以及对许多革兰氏阴性病原体中的毒力重要的其他基因。PhoQ是一种传感器激酶，磷酸化并激活转录因子PhoP。由于反馈抑制是一个共同的主题，在应激反应电路，我们假设，一些成员的PhoP调节子可能发挥这样的作用，在PhoQ/PhoP通路。因此，我们筛选了在该系统中介导反馈的PhoP调节基因。我们发现，缺失mgrB（yobG），它编码一个47个氨基酸的肽，导致在一个有效的增加PhoP调节的转录。此外，在高浓度和低浓度的镁下，mgrB的过度表达都降低了转录。定位和细菌双杂交研究表明，MgrB驻留在内膜，并直接与PhoQ相互作用。我们进一步表明，鼠伤寒沙门氏菌和鼠疫耶尔森氏菌的MgrB同源物也抑制PhoP调控的转录在这些生物体。在细胞调节回路中，反馈已经与响应于刺激而调节诱导动力学和/或细胞间变异性相关联。有趣的是，我们发现消除MgrB介导的反馈对报告蛋白产生的动力学没有显著影响，并且没有降低细胞间表达的变异性。我们的研究结果表明，MgrB是一个广泛保守的膜肽，是一个关键的负反馈介质中的PhoQ/PhoP电路。这种新的调节器可以作为一个控制点，整合额外的输入信号，以调节这一重要信号系统的活动。蛋白质PhoQ和PhoP组成了一个环境传感系统，该系统已在许多细菌中得到广泛研究，包括鼠伤寒沙门氏菌和大肠杆菌。PhoQ/PhoP系统受到低胞外镁或某些阳离子抗菌肽存在的条件的刺激;它控制基因，其蛋白质产物在这些条件下保护细胞或在调节病原体毒力方面发挥其他关键作用。然而，PhoP调节子的许多成员的功能仍然是未知的。这使得开放的可能性，一些PhoP调节基因可能介导反馈在这个系统中。允许适应环境变化的调节回路通常利用负反馈来实现适当的响应水平。为了寻找负反馈，我们在大肠杆菌中筛选了PhoP调控基因的敲除。杆菌我们已经确定了一个非常小的膜蛋白，只有47个氨基酸，介导了有效的负反馈的PhoQ/PhoP电路在E。coli、S.鼠伤寒、鼠疫耶尔森氏菌和其他可能的相关细菌。这代表了一个小的，容易被忽视的开放阅读框架，在调节广泛保守的信号转导通路中起着关键作用的一个引人注目的例子。
The PhoQ/PhoP signaling system responds to low magnesium and the presence of certain cationic antimicrobial peptides. It regulates genes important for growth under these conditions, as well as additional genes important for virulence in many gram-negative pathogens. PhoQ is a sensor kinase that phosphorylates and activates the transcription factor PhoP. Since feedback inhibition is a common theme in stress-response circuits, we hypothesized that some members of the PhoP regulon may play such a role in the PhoQ/PhoP pathway. We therefore screened for PhoP-regulated genes that mediate feedback in this system. We found that deletion of mgrB (yobG), which encodes a 47 amino acid peptide, results in a potent increase in PhoP-regulated transcription. In addition, over-expression of mgrB decreased transcription at both high and low concentrations of magnesium. Localization and bacterial two-hybrid studies suggest that MgrB resides in the inner-membrane and interacts directly with PhoQ. We further show that MgrB homologs from Salmonella typhimurium and Yersinia pestis also repress PhoP-regulated transcription in these organisms. In cell regulatory circuits, feedback has been associated with modulating the induction kinetics and/or the cell-to-cell variability in response to stimulus. Interestingly, we found that elimination of MgrB-mediated feedback did not have a significant effect on the kinetics of reporter protein production and did not decrease the variability in expression among cells. Our results indicate MgrB is a broadly conserved membrane peptide that is a critical mediator of negative feedback in the PhoQ/PhoP circuit. This new regulator may function as a point of control that integrates additional input signals to modulate the activity of this important signaling system. The proteins PhoQ and PhoP comprise an environmental sensing system that has been extensively studied in numerous bacteria, including Salmonella typhimurium and Escherichia coli. The PhoQ/PhoP system is stimulated by conditions of low extracellular magnesium or the presence of certain cationic antimicrobial peptides; and it controls genes, whose protein products protect the cell under these conditions or play other critical roles in regulating the virulence of pathogens. The functions of many members of the PhoP regulon, however, remain uncharacterized. This leaves open the possibility that some PhoP-regulated genes may mediate feedback in this system. Regulatory circuits that allow adaptation to environmental change often make use of negative feedback to achieve the appropriate level of response. To look for negative feedback, we screened knockouts of PhoP-regulated genes in E. coli. We have identified a remarkably small membrane protein of just 47 amino acids that mediates potent negative feedback on the PhoQ/PhoP circuit in E. coli, S. typhimurium, Yersinia pestis, and likely other related bacteria. This represents a striking example of a small, easily-overlooked open reading frame that plays a critical role in regulating a broadly conserved signal transduction pathway.
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