Dissection of the molecular circuitry controlling virulence in Francisella tularensis.
Dissection of the molecular circuitry controlling virulence in Francisella tularensis.
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DOI：
10.1101/gad.303701.117
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发表时间：
2017-08-01
影响因子：
10.5
通讯作者：
Schumacher MA
中科院分区：
文献类型：
--
作者：
Cuthbert BJ;Ross W;Rohlfing AE;Dove SL;Gourse RL;Brennan RG;Schumacher MA
Cuthbert等人。鉴定MglA-SSPA是一种新的ppGpp结合复合体，并描述了apo和ppGpp结合的MglA-SSPA的结构。图拉氏方济氏菌是图拉热症的病原体，是已知的最具传染性的细菌之一。由于其极强的致病性，图拉氏丝虫被美国政府列为A类生物武器。图拉氏方丝酵母的毒力来源于方济氏菌致病岛(FPI)上编码的基因。一组不同寻常的Francisella调节器--异构体巨噬细胞生长位点蛋白A(MglA)-严格的饥饿蛋白A(SSPA)复合体和DNA结合蛋白致病岛基因调节器(PigR)-激活FPI转录，因此对毒力是必不可少的。有趣的是，在感染过程中产生的第二信使鸟苷-四磷酸(PpGpp)也参与协调弗朗西斯氏菌的毒力；然而，它的作用尚不清楚。在这里，我们确定MglA-SSPA是一种新的ppGpp结合络合物，并描述了apo和ppGpp结合的MglA-SSPA的结构。我们证明了与RNA聚合酶(RNAP)结合的MglA-SSPA也与PigR的C-末端结构域相互作用，从而将(MglA-SSPA)-RNAP复合体锚定在FPI启动子上。此外，我们证明了MglA-SSPA必须与ppGpp结合才能介导与PigR的高亲和力相互作用。因此，这些研究揭示了一种不同于先前描述的ppGpp转录调控的新途径。数据还表明，图拉氏F菌的致病机制是由高度相互连接的分子电路控制的，在该电路中，毒力机制通过小分子应激信号直接感受感染。
Cuthbert et al. identify MglA–SspA as a novel ppGpp-binding complex and describe structures of apo- and ppGpp-bound MglA–SspA. Francisella tularensis, the etiological agent of tularemia, is one of the most infectious bacteria known. Because of its extreme pathogenicity, F. tularensis is classified as a category A bioweapon by the US government. F. tularensis virulence stems from genes encoded on the Francisella pathogenicity island (FPI). An unusual set of Francisella regulators—the heteromeric macrophage growth locus protein A (MglA)–stringent starvation protein A (SspA) complex and the DNA-binding protein pathogenicity island gene regulator (PigR)—activates FPI transcription and thus is essential for virulence. Intriguingly, the second messenger, guanosine–tetraphosphate (ppGpp), which is produced during infection, is also involved in coordinating Francisella virulence; however, its role has been unclear. Here we identify MglA–SspA as a novel ppGpp-binding complex and describe structures of apo- and ppGpp-bound MglA–SspA. We demonstrate that MglA–SspA, which binds RNA polymerase (RNAP), also interacts with the C-terminal domain of PigR, thus anchoring the (MglA–SspA)–RNAP complex to the FPI promoter. Furthermore, we show that MglA–SspA must be bound to ppGpp to mediate high-affinity interactions with PigR. Thus, these studies unveil a novel pathway different from those described previously for regulation of transcription by ppGpp. The data also indicate that F. tularensis pathogenesis is controlled by a highly interconnected molecular circuitry in which the virulence machinery directly senses infection via a small molecule stress signal.
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影响因子：
3.7
作者：
Cuthbert BJ;Brennan RG;Schumacher MA
通讯作者：
Schumacher MA
影响因子：
3.7
作者：
Atkinson GC;Tenson T;Hauryliuk V
通讯作者：
Hauryliuk V
影响因子：
3.1
作者：
Faron, Matthew;Fletcher, Joshua R.;Jones, Bradley D.
通讯作者：
Jones, Bradley D.
影响因子：
3.2
作者：
Nano, FE;Zhang, N;Elkins, KL
通讯作者：
Elkins, KL
影响因子：
16
作者：
Liu, Kuanqing;Myers, Angela R.;Pisithkul, Tippapha;Claas, Kathy R.;Satyshur, Kenneth A.;Amador-Noguez, Daniel;Keck, James L.;Wang, Jue D.
通讯作者：
Wang, Jue D.