The role of coupled positive feedback in the expression of the SPI1 type three secretion system in Salmonella.
The role of coupled positive feedback in the expression of the SPI1 type three secretion system in Salmonella.
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DOI：
10.1371/journal.ppat.1001025
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发表时间：
2010-07-29
期刊：
影响因子：
6.7
通讯作者：
Rao CV
中科院分区：
文献类型：
--
作者：
Saini S;Ellermeier JR;Slauch JM;Rao CV
鼠伤寒沙门氏菌（Salmonella enterica serovar Typhimurium）是一种常见的食源性病原体，其使用沙门氏菌致病岛1（SPI1）中编码的3型分泌系统（T3SS）诱导炎性腹泻并侵入肠上皮细胞。编码SPI1 T3SS的基因受到相互作用的转录调控因子网络的严格调控，该网络涉及三个耦合的正反馈环。虽然SPI1基因电路的核心结构已经确定，但这些相互作用的调节器和相关反馈回路的相对作用仍然未知。为了确定这个电路的功能，我们测量了基因表达动力学在人口和单细胞分辨率在一些SPI1调节突变体。利用这些数据，我们构建了SPI1基因电路的数学模型。对模型的分析预测，该电路具有两个功能。第一个是对SPI1激活设置阈值，确保编码T3SS的基因仅在响应环境和细胞提示的适当组合时表达。二是扩增SPI1基因表达。为了实验测试这些预测，我们通过改变其调控结构来重新连接SPI1遗传电路。这使我们能够通过改变激活信号的强度和动态来直接测试我们对电路功能的预测。总的来说，我们的实验和计算结果使我们能够解构这个复杂的电路，并确定其各个组成部分在调节SPI1基因表达动态中的作用。 沙门氏菌是人类多种疾病的病原体，包括胃肠炎和肠热病。感染过程中的一个关键步骤发生在沙门氏菌使用分子皮下注射针侵入肠上皮细胞时。沙门氏菌使用这些针将蛋白质注入宿主细胞，使细菌能够进入并在其中复制。这些针的产生，以及入侵宿主的必然决定，受到相互作用的调节蛋白的复杂网络的严格控制，当单独研究时，似乎具有冗余或拮抗作用。为了了解这些调控因子如何动态地控制这些入侵基因的表达，我们系统地解构了网络，然后利用这些信息通过计算机模拟来分析它们的复合行为。我们的分析表明，这种调控网络确保了只有当入侵信号（环境和细胞信号的组合）超过一个确定的阈值时，入侵基因才会表达。一旦被诱导，该网络进一步放大并加速入侵基因的表达。这些结果进一步揭示了感染过程中的一个关键机制，即入侵的决定，从而加深了我们对这种重要病原体的理解。
Salmonella enterica serovar Typhimurium is a common food-borne pathogen that induces inflammatory diarrhea and invades intestinal epithelial cells using a type three secretion system (T3SS) encoded within Salmonella pathogenicity island 1 (SPI1). The genes encoding the SPI1 T3SS are tightly regulated by a network of interacting transcriptional regulators involving three coupled positive feedback loops. While the core architecture of the SPI1 gene circuit has been determined, the relative roles of these interacting regulators and associated feedback loops are still unknown. To determine the function of this circuit, we measured gene expression dynamics at both population and single-cell resolution in a number of SPI1 regulatory mutants. Using these data, we constructed a mathematical model of the SPI1 gene circuit. Analysis of the model predicted that the circuit serves two functions. The first is to place a threshold on SPI1 activation, ensuring that the genes encoding the T3SS are expressed only in response to the appropriate combination of environmental and cellular cues. The second is to amplify SPI1 gene expression. To experimentally test these predictions, we rewired the SPI1 genetic circuit by changing its regulatory architecture. This enabled us to directly test our predictions regarding the function of the circuit by varying the strength and dynamics of the activating signal. Collectively, our experimental and computational results enable us to deconstruct this complex circuit and determine the role of its individual components in regulating SPI1 gene expression dynamics. Salmonella is a causative agent for a wide range of diseases in humans, including gastroenteritis and enteric fever. A key step in the infection process occurs when Salmonella invades intestinal epithelial cells using a molecular hypodermic needle. Salmonella uses these needles to inject proteins into host cells that enable the bacterium to enter and replicate within them. The production of these needles, and the corollary decision to invade the host, is tightly controlled by a complex network of interacting regulatory proteins that, when studied individually, seemingly have either redundant or antagonizing effects. To understand how this ensemble of regulators dynamically controls the expression of these invasion genes, we systematically deconstructed the network and then used this information to analyze their composite behavior by computer simulation. Our analysis demonstrates that this regulatory network ensures that the invasion genes are expressed only when the invasion signals, a combination of environmental and cellular cues, exceed a defined threshold. Once induced, this network further amplifies and accelerates the expression of the invasion genes. These results further our understanding of this important pathogen by unraveling a key mechanism during infection, namely the decision to invade.
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影响因子：
3.5
作者：
CHEREPANOV, PP;WACKERNAGEL, W
通讯作者：
WACKERNAGEL, W
影响因子：
11.4
作者：
Darwin, KH;Miller, VL
通讯作者：
Miller, VL
DOI：
10.1084/jem.139.5.1189
发表时间：
1974-05-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Carter PB;Collins FM
通讯作者：
Collins FM
影响因子：
3.6
作者：
Darwin, KH;Miller, VL
通讯作者：
Miller, VL
影响因子：
3.6
作者：
Bajaj, V;Hwang, C;Lee, CA
通讯作者：
Lee, CA