The virulence-associated twocomponent PhoP-PhoR system controls the biosynthesis of polyketide-derived lipids in Mycobacterium tuberculosis
The virulence-associated twocomponent PhoP-PhoR system controls the biosynthesis of polyketide-derived lipids in Mycobacterium tuberculosis
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DOI：
10.1074/jbc.c500388200
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发表时间：
2006-01-20
影响因子：
4.8
通讯作者：
Jackson, M
中科院分区：
文献类型：
--
作者：
Asensio, JG;Maia, C;Jackson, M
双组分调节信号转导系统是原核生物对各种环境刺激的适应性反应的重要组成部分。php - phor在结核分枝杆菌中的破坏显著减弱毒力，这意味着该系统直接和/或间接协调重要毒力因子的表达，其身份仍有待确定。有趣的是，在敲除结核分枝杆菌Mt103的php - phor双组分系统时，突变菌株的群体形态、特征和对碱性染料中性红的反应性发生了巨大变化，这些都是已知与毒力相关的结核杆菌的固有特性。由于突变体形成蛇形索和染色能力的不足可能是其细胞包膜组成改变的结果，我们开始分析两种不同结核分枝杆菌中构建的phoP和phoP- phor突变体的脂质含量。我们的研究结果表明，PhoP协调并积极调节甲基支链脂肪酸的酰基海藻糖的合成，已知这种合成仅限于结核分枝杆菌复合体的致病性物种，即二酰基海藻糖、聚酰基海藻糖和脂肪酸。也有证据表明，产生这些脂质需要PhoP，而不需要PhoR。这项工作是迈向php - phor功能表征和了解结核分枝杆菌复杂脂质合成的重要一步。
Two-component regulatory signal transduction systems are important elements of the adaptative response of prokaryotes to a variety of environmental stimuli. Disruption of PhoP-PhoR in Mycobacterium tuberculosis dramatically attenuates virulence, implying that this system directly and/or indirectly coordinates the expression of important virulence factors whose identity remains to be established. Interestingly, in knocking-out the PhoP-PhoR two-component system in M. tuberculosis Mt103, dramatic changes in the colonial morphology, cording properties, and reactivity of the mutant strain to the basic dye neutral red, all intrinsic properties of tubercle bacilli known to correlate with virulence, were noted. Because deficiencies in the ability of the mutant to form serpentine cords and stain with the dye are likely the results of alterations of its cell envelope composition, we undertook to analyze the lipid content of phoP and phoP-phoR mutants constructed in two different strains of M. tuberculosis. Our results indicate that PhoP coordinately and positively regulates the synthesis of methyl-branched fatty acid-containing acyltrehaloses known to be restricted to pathogenic species of the M. tuberculosis complex, namely diacyltrehaloses, polyacyltrehaloses, and sulfolipids. Evidence is also provided that PhoP but not PhoR is required for the production of these lipids. This work represents an important step toward the functional characterization of PhoP-PhoR and the understanding of complex lipid synthesis in M. tuberculosis.