A mycobacterium ESX-1-secreted virulence factor with unique requirements for export.
A mycobacterium ESX-1-secreted virulence factor with unique requirements for export.
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DOI：
10.1371/journal.ppat.0030105
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发表时间：
2007-08-03
期刊：
影响因子：
6.7
通讯作者：
Brown EJ
中科院分区：
文献类型：
--
作者：
McLaughlin B;Chon JS;MacGurn JA;Carlsson F;Cheng TL;Cox JS;Brown EJ
病原菌的专门分泌系统通常运输多种效应物，这些效应物协同作用以控制和利用宿主细胞作为复制许可的小生境。海分枝杆菌和结核分枝杆菌基因组都含有一个扩展的差异区1（extRD 1）基因座，该基因座编码一种这样的途径，即早期分泌抗原靶点6（ESAT-6）系统1（ESX-1）分泌装置。ESX-1是毒力和分泌蛋白质ESAT-6、培养滤液蛋白10（CFP-10）和EspA所必需的。在这里，我们发现Rv 3881 c和它的M. marinum同源物Mh 3881 c是分泌蛋白，在任一生物体中RD 1的破坏都会阻断分泌。我们已将Rv 3881 c/Mh 3881 c基因espB重命名为ESX-1底物蛋白B。M的分泌。Marinum EspB（EspBM）需要RD 1内的Mh 3879 c和Mh 3871基因，而CFP-10分泌不受Mh 3879 c破坏的影响。相比之下，extRD 1基因座内Mh 3866或Mh 3867的破坏阻止CFP-10分泌而不影响EspBM。仅不能分泌EspBM或仅不能分泌CFP-10的突变体在巨噬细胞中比不能分泌两种底物的突变体减弱更少。EspBM与Mh 3879 c发生物理相互作用;结核病同源物EspBT与Rv 3879 c物理相互作用;不能结合Mh 3879 c的EspBM突变体不能分泌。我们还发现Rv 3879 c和Rv 3871（ESX-1机器的一个组件）之间的相互作用，表明EspB的分泌机制。结果确定EspB是巨噬细胞中毒力和生长所需的ESX-1底物，并表明ESX-1对毒力的贡献可能来自多种独立底物的分泌。致病菌使宿主防御失效的主要机制是分泌毒力蛋白。这些效应物通常由专门的分泌机器运输。存在于分枝杆菌和其他革兰氏阳性属中的一种这样的途径是ESX-1（早期分泌抗原靶6系统1）。尽管ESX-1是与感染发病机制相关的多种表型所必需的，但迄今为止仅确定了分泌机器的三种底物，并且不了解这些底物输出的机制。在我们努力了解这种毒性相关的分泌机制，我们确定了一种新的基板，并发现其交付的ESX-1机器需要不同的蛋白质相互作用比以前确定的基板。最后，我们提出的数据表明，各种ESX-1基板有助于加性的毒力。将这些数据纳入ESX-1功能模型。
Specialized secretion systems of pathogenic bacteria commonly transport multiple effectors that act in concert to control and exploit the host cell as a replication-permissive niche. Both the Mycobacterium marinum and the Mycobacterium tuberculosis genomes contain an extended region of difference 1 (extRD1) locus that encodes one such pathway, the early secretory antigenic target 6 (ESAT-6) system 1 (ESX-1) secretion apparatus. ESX-1 is required for virulence and for secretion of the proteins ESAT-6, culture filtrate protein 10 (CFP-10), and EspA. Here, we show that both Rv3881c and its M. marinum homolog, Mh3881c, are secreted proteins, and disruption of RD1 in either organism blocks secretion. We have renamed the Rv3881c/Mh3881c gene espB for ESX-1 substrate protein B. Secretion of M. marinum EspB (EspBM) requires both the Mh3879c and Mh3871 genes within RD1, while CFP-10 secretion is not affected by disruption of Mh3879c. In contrast, disruption of Mh3866 or Mh3867 within the extRD1 locus prevents CFP-10 secretion without effect on EspBM. Mutants that fail to secrete only EspBM or only CFP-10 are less attenuated in macrophages than mutants failing to secrete both substrates. EspBM physically interacts with Mh3879c; the M. tuberculosis homolog, EspBT, physically interacts with Rv3879c; and mutants of EspBM that fail to bind Mh3879c fail to be secreted. We also found interaction between Rv3879c and Rv3871, a component of the ESX-1 machine, suggesting a mechanism for the secretion of EspB. The results establish EspB as a substrate of ESX-1 that is required for virulence and growth in macrophages and suggests that the contribution of ESX-1 to virulence may arise from the secretion of multiple independent substrates. A major mechanism used by pathogenic bacteria for disabling host defenses is secretion of virulence proteins. These effectors are often transported by specialized secretion machines. One such pathway, present in Mycobacterium and other Gram-positive genera, is ESX-1 (early secretory antigenic target 6 system 1). Although ESX-1 is required for multiple phenotypes related to the pathogenesis of infection, only three substrates of the secretion machine have been identified to date, and the mechanism by which these substrates are exported is not understood. In our efforts to understand this virulence-related secretion mechanism, we identified a novel substrate and found that its delivery to the ESX-1 machine requires different protein interactions than previously identified substrates. Finally, we present data that the various ESX-1 substrates contribute additively to virulence. These data are incorporated into a model of ESX-1 function.
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影响因子：
3.2
作者：
Okkels, LM;Andersen, P
通讯作者：
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影响因子：
3.1
作者：
RATLIFF, TL;MCCARTHY, R;BROWN, EJ
通讯作者：
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影响因子：
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作者：
Baulard, AR;Gurcha, SS;Besra, GS
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影响因子：
3.6
作者：
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通讯作者：
Brown, EJ
DOI：
10.1073/pnas.0504922102
发表时间：
2005-07-26
影响因子：
11.1
作者：
Fortune, SM;Jaeger, A;Rubin, EJ
通讯作者：
Rubin, EJ