MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis
MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis
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DOI：
10.1371/journal.ppat.1006088
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发表时间：
2016-12-01
期刊：
影响因子：
6.7
通讯作者：
Ivanov, Stanimir S.
中科院分区：
文献类型：
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作者：
Abshire, Camille F.;Dragoi, Ana-Maria;Ivanov, Stanimir S.
细菌病原体被保护在独特的膜结合细胞器内，这些细胞器随着时间的推移而膨胀以支持细菌复制。这些隔室隔离细菌分子，使其远离诱导抗菌反应的宿主胞质免疫监视途径。人类肺部病原体嗜肺军团菌维持生态位稳态的机制知之甚少。我们发现，军团菌的空泡（LCV）需要一个持续的供应过程中扩大的主机脂质。脂质缺乏导致LCV破裂和启动宿主细胞死亡反应，而过量的宿主脂质增加LCV的大小和住房能力。我们发现从血清中摄取脂质和从头脂肪生成是军团菌感染的巨噬细胞膜生物合成的不同冗余供应机制。在感染过程中，代谢检查点激酶雷帕霉素机制靶点（MTOR）通过血清反应元件结合蛋白1和2（SREBP 1/2）转录因子控制脂肪生成。在军团菌感染的巨噬细胞中，需要Toll样受体（TLR）衔接蛋白的宿主驱动的反应抑制了MTOR信号传导，这反过来使血清饥饿下的LCV不稳定。宿主MTOR抑制通路的失活揭示了L。嗜肺菌通过需要上游调节剂磷脂酰肌醇-4，5-二磷酸3-激酶（PI 3 K）和一种或多种Dot/Icm效应蛋白的过程在其整个细胞内感染周期中维持MTOR信号传导。军团菌持续的MTOR信号通过药理学或遗传干扰或通过激活宿主MTOR抑制反应促进LCV扩增和PI 3 K-MTOR-SREPB 1/2轴的抑制，使扩增的LCV不稳定，这反过来触发了受感染的巨噬细胞的细胞死亡。我们的工作确定了LCV稳态的宿主代谢要求，并证明了L。嗜肺菌已经进化为操纵MTOR依赖性脂肪生成以实现最佳细胞内复制。
Vacuolar bacterial pathogens are sheltered within unique membrane-bound organelles that expand over time to support bacterial replication. These compartments sequester bacterial molecules away from host cytosolic immunosurveillance pathways that induce antimicrobial responses. The mechanisms by which the human pulmonary pathogen Legionella pneumophila maintains niche homeostasis are poorly understood. We uncovered that the Legionella-containing vacuole (LCV) required a sustained supply of host lipids during expansion. Lipids shortage resulted in LCV rupture and initiation of a host cell death response, whereas excess of host lipids increased LCVs size and housing capacity. We found that lipids uptake from serum and de novo lipogenesis are distinct redundant supply mechanisms for membrane biogenesis in Legionella-infected macrophages. During infection, the metabolic checkpoint kinase Mechanistic Target of Rapamycin (MTOR) controlled lipogenesis through the Serum Response Element Binding Protein 1 and 2 (SREBP1/2) transcription factors. In Legionella-infected macrophages a host-driven response that required the Toll-like receptors (TLRs) adaptor protein Myeloid differentiation primary response gene 88 (Myd88) dampened MTOR signaling which in turn destabilized LCVs under serum starvation. Inactivation of the host MTOR-suppression pathway revealed that L. pneumophila sustained MTOR signaling throughout its intracellular infection cycle by a process that required the upstream regulator Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and one or more Dot/Icm effector proteins. Legionella-sustained MTOR signaling facilitated LCV expansion and inhibition of the PI3K-MTOR-SREPB1/2 axis through pharmacological or genetic interference or by activation of the host MTOR-suppression response destabilized expanding LCVs, which in turn triggered cell death of infected macrophages. Our work identified a host metabolic requirement for LCV homeostasis and demonstrated that L. pneumophila has evolved to manipulate MTOR-dependent lipogenesis for optimal intracellular replication.