Mutations in ppe38 block PE_PGRS secretion and increase virulence of Mycobacterium tuberculosis
Mutations in ppe38 block PE_PGRS secretion and increase virulence of Mycobacterium tuberculosis
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DOI：
10.1038/s41564-017-0090-6
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发表时间：
2018-02-01
影响因子：
28.3
通讯作者：
Bitter, Wilbert
中科院分区：
文献类型：
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作者：
Ates, Louis S.;Dippenaar, Anzaan;Bitter, Wilbert
结核分枝杆菌需要大量的分泌和输出蛋白质用于其毒力、免疫调节和营养摄取。这些蛋白质中的大多数通过不同的VII型分泌系统转运（1，2）。最近进化的VII型分泌系统ESX-5分泌数十种属于PE和PPE家族的底物，其以靠近氨基末端的保守脯氨酸和谷氨酸残基命名（3，4）。然而，这些蛋白质的作用在很大程度上仍然是难以捉摸的（1）。在这里，我们表明ppe 38的突变完全阻断了ESX-5底物的两个大子集的分泌，即PPE-MPTR和PE_PGRS，它们共同包含> 80种蛋白质。重要的是，高毒力临床M.北京谱系的结核菌株具有这样的突变和伴随的分泌物损失（5）。PPE 38依赖性分泌的恢复部分地恢复了北京株的强毒力表型，而中等毒力M.结核病增加了毒力。这表明这些ESX-5底物在毒力衰减中具有重要作用。系统发育分析显示，ppe 38的缺失发生在“现代”北京亚系的分支点，并且为世界范围内的北京暴发菌株所共有，这表明这种缺失可能有助于它们的成功和全球分布（6，7）。
Mycobacterium tuberculosis requires a large number of secreted and exported proteins for its virulence, immune modulation and nutrient uptake. Most of these proteins are transported by the different type VII secretion systems(1,2). The most recently evolved type VII secretion system, ESX-5, secretes dozens of substrates belonging to the PE and PPE families, which are named for conserved proline and glutamic acid residues close to the amino terminus(3,4). However, the role of these proteins remains largely elusive(1). Here, we show that mutations of ppe38 completely block the secretion of two large subsets of ESX-5 substrates, that is, PPE-MPTR and PE_PGRS, together comprising > 80 proteins. Importantly, hypervirulent clinical M. tuberculosis strains of the Beijing lineage have such a mutation and a concomitant loss of secretion(5). Restoration of PPE38-dependent secretion partially reverted the hypervirulence phenotype of a Beijing strain, and deletion of ppe38 in moderately virulent M. tuberculosis increased virulence. This indicates that these ESX-5 substrates have an important role in virulence attenuation. Phylogenetic analysis revealed that deletion of ppe38 occurred at the branching point of the 'modern' Beijing sublineage and is shared by Beijing outbreak strains worldwide, suggesting that this deletion may have contributed to their success and global distribution(6,7).