Direct transcriptional control of the plasminogen activator gene of Yersinia pestis by the cyclic AMP receptor protein
Direct transcriptional control of the plasminogen activator gene of Yersinia pestis by the cyclic AMP receptor protein
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DOI：
10.1128/jb.00972-07
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发表时间：
2007-12-01
影响因子：
3.2
通讯作者：
Young, Glenn M.
中科院分区：
文献类型：
--
作者：
Kim, Tae-Jong;Chauhan, Sadhana;Young, Glenn M.
水平基因转移事件之后的适当的基因调控整合推动了细菌病原体的快速进化。鼠疫耶尔森氏菌在进化过程中的一个关键事件是获得了携带纤溶酶原激活物基因pla的pPCP1。这增加了细菌从跳蚤叮咬部位的传播，并在肺炎感染期间顺便增加了呼吸道的复制，从而促进了该病的腺泡性形式。我们确定pla的表达受全球调节因子cAMP(CAMP)受体蛋白(CRP)的调控。这种转录因子在远亲细菌中非常保守，它作为无处不在的信号分子cAMP的可溶性受体，控制着代谢和应激保护基因的全球网络。C反应蛋白在鼠疫杆菌中具有相似的生理作用，因为其功能的丧失导致不能代谢各种非葡萄糖底物。PLA表达的激活需要PLA启动子的转录激活元件作为CRP结合位点。CRP与此部位的相互作用仅在cAMP存在的情况下发生。C反应蛋白结合位点核苷酸序列的改变在体外阻止了C反应蛋白-DNA复合体的形成，并抑制了体内PLA的表达。将PLA置于CRP的直接调控下，突显了高度适应的病原体如何整合横向获得的基因，以协调毒力因子的表达与全球基因网络，从而在感染生命周期中维持动态平衡。
Horizontal gene transfer events followed by proper regulatory integration of a gene drive rapid evolution of bacterial pathogens. A key event in the evolution of the highly virulent plague bacterium Yersinia pestis was the acquisition of plasmid pPCP1, which carries the plasminogen activator gene, pla. This promoted the bubonic form of the disease by increasing bacterial dissemination from flea bite sites and incidentally enhanced replication in respiratory airways during pneumonic infection. We determined that expression of pla is controlled by the global regulator cyclic AMP (cAMP) receptor protein (Crp). This transcription factor is well conserved among distantly related bacteria, where it acts as a soluble receptor for the ubiquitous signaling molecule cAMP and controls a global network of metabolic and stress-protective genes. Crp has a similar physiological role in Y. pestis since loss of its function resulted in an inability to metabolize a variety of nonglucose substrates. Activation of pla expression requires a transcription activation element of the pla promoter that serves as a Crp binding site. Crp interaction with this site was demonstrated to occur only in the presence of cAMP. Alteration of the Crp binding site nucleotide sequence prevented in vitro formation of Crp-DNA complexes and inhibited in vivo expression of pla. The placement of pla under direct regulatory control of Crp highlights how highly adapted pathogens integrate laterally acquired genes to coordinate virulence factor expression with global gene networks to maintain homeostasis through the infectious life cycle.