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鉴定新型柯克斯体 Icm/Dot 效应因子及其在调节丝裂原活化蛋白激酶途径中的作用的遗传分析。

Identification of novel Coxiella burnetii Icm/Dot effectors and genetic analysis of their involvement in modulating a mitogen-activated protein kinase pathway.

机构信息

Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

出版信息

Infect Immun. 2014 Sep;82(9):3740-52. doi: 10.1128/IAI.01729-14. Epub 2014 Jun 23.

Abstract

Coxiella burnetii, the causative agent of Q fever, is a human intracellular pathogen that utilizes the Icm/Dot type IVB secretion system to translocate effector proteins into host cells. To identify novel C. burnetii effectors, we applied a machine-learning approach to predict C. burnetii effectors, and examination of 20 such proteins resulted in the identification of 13 novel effectors. To determine whether these effectors, as well as several previously identified effectors, modulate conserved eukaryotic pathways, they were expressed in Saccharomyces cerevisiae. The effects on yeast growth were examined under regular growth conditions and in the presence of caffeine, a known modulator of the yeast cell wall integrity (CWI) mitogen-activated protein (MAP) kinase pathway. In the presence of caffeine, expression of the effectors CBU0885 and CBU1676 caused an enhanced inhibition of yeast growth, and the growth inhibition of CBU0388 was suppressed. Furthermore, analysis of synthetic lethality effects and examination of the activity of the CWI MAP kinase transcription factor Rlm1 indicated that CBU0388 enhances the activation of this MAP kinase pathway in yeast, while CBU0885 and CBU1676 abolish this activation. Additionally, coexpression of CBU1676 and CBU0388 resulted in mutual suppression of their inhibition of yeast growth. These results strongly indicate that these three effectors modulate the CWI MAP kinase pathway in yeast. Moreover, both CBU1676 and CBU0885 were found to contain a conserved haloacid dehalogenase (HAD) domain, which was found to be required for their activity. Collectively, our results demonstrate that MAP kinase pathways are most likely targeted by C. burnetii Icm/Dot effectors.

摘要

贝氏考克斯体是 Q 热的病原体,是一种利用 Icm/Dot 型 IVB 分泌系统将效应蛋白转运入宿主细胞的人类细胞内病原体。为了鉴定新的贝氏考克斯体效应蛋白,我们应用机器学习方法预测贝氏考克斯体效应蛋白,对 20 种此类蛋白的检测导致鉴定出 13 种新的效应蛋白。为了确定这些效应蛋白以及几种先前鉴定的效应蛋白是否调节保守的真核途径,我们在酿酒酵母中表达了它们。在常规生长条件下和在咖啡因存在下(一种已知的酵母细胞壁完整性(CWI)丝裂原激活蛋白(MAP)激酶途径调节剂),检查了对酵母生长的影响。在咖啡因存在下,效应蛋白 CBU0885 和 CBU1676 的表达导致酵母生长的抑制增强,而 CBU0388 的生长抑制被抑制。此外,分析合成致死效应并检查 CWI MAP 激酶转录因子 Rlm1 的活性表明,CBU0388 增强了该 MAP 激酶途径在酵母中的激活,而 CBU0885 和 CBU1676 则消除了这种激活。此外,CBU1676 和 CBU0388 的共表达导致它们对酵母生长抑制的相互抑制。这些结果强烈表明,这三种效应蛋白调节酵母中的 CWI MAP 激酶途径。此外,发现 CBU1676 和 CBU0885 均含有保守的卤酸脱卤酶(HAD)结构域,该结构域对于它们的活性是必需的。总的来说,我们的结果表明,MAP 激酶途径很可能是贝氏考克斯体 Icm/Dot 效应蛋白的靶标。

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