Bile acids induce cholera toxin expression in Vibrio cholerae in a ToxT-independent manner
Bile acids induce cholera toxin expression in Vibrio cholerae in a ToxT-independent manner
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DOI：
10.1073/pnas.0409559102
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发表时间：
2005-02-22
影响因子：
11.1
通讯作者：
Mekalanos, JJ
中科院分区：
文献类型：
--
作者：
Hung, DT;Mekalanos, JJ
霍乱弧菌感染期间产生的霍乱毒素（CT）导致霍乱的特征性腹泻。跨膜蛋白ToxR最初被鉴定为异源大肠杆菌系统中ctxAB的功能性转录激活因子。然而，霍乱弧菌中ctxAB启动子的直接ToxR激活先前尚未得到证实。相反，已经定义了一种调节级联，其中激活剂ToxRS和TcpPH通过协同作用以转录激活另一种调节剂ToxT来调节ctxAB表达。反过来，ToxT直接激活ctxAB表达以及tcp基因和其他毒力相关基因的表达。在这项研究中，我们表明，ToxRS直接激活ctxAB在一个经典的生物型霍乱弧菌的ToxT-独立的方式，这种激活需要胆汁酸的存在。虽然由该机制诱导的CT水平低于在其他体外条件下诱导的水平，但本文所述的胆汁依赖性条件更具生理性，不依赖于pH和温度。我们进一步表明，胆汁酸不能刺激ToxRS依赖性表达的CT在El Tor生物型菌株与经典和El Tor ctxAB启动子之间的差异，不同的七肽TTTTGAT重复在其各自的上游区域。胆汁酸通过ToxRS刺激ctxAB直接活化的能力取决于ToxR的跨膜结构域，其可与胆总管弧菌内膜中的胆汁酸相互作用。
The production of cholera toxin (CT) during Vibrio cholerae infection results in the hallmark diarrhea that characterizes the disease cholera. The transmembrane protein ToxR was originally identified as a functional transcriptional activator of ctxAB in a heterologous Escherichia coli system. However, direct ToxR activation of the ctxAB promoter in V. cholerae has not been previously demonstrated. Instead, a regulatory cascade has been defined in which the activators ToxRS and TcpPH modulate ctxAB expression by acting in concert to transcriptionally activate another regulator, ToxT. ToxT, in turn, directly activates ctxAB expression as well as expression of the tcp genes and other virulence-associated genes. In this study, we show that ToxRS directly activates ctxAB in a ToxT-independent manner in a classical biotype V. cholerae, and that this activation requires the presence of bile acids. Although the levels of CT induced by this mechanism are lower than levels induced under other in vitro conditions, the bile-dependent conditions described here are more physiologic, being independent of pH and temperature. We further show that the inability of bile acids to stimulate ToxRS-dependent expression of CT in El Tor biotype strains is related to the differences between classical and El Tor ctxAB promoters, which differ in the number of heptad TTTTGAT repeats in their respective upstream regions. The ability of bile acids to stimulate direct activation of ctxAB by ToxRS depends upon the transmembrane domain of ToxR, which may interact with bile acids in the inner membrane of V. cholerae.