Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1.
Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1.
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DOI：
10.1016/j.chom.2018.04.006
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发表时间：
2018-05-09
影响因子：
30.3
通讯作者：
Blanke SR
中科院分区：
文献类型：
--
作者：
Kim IJ;Lee J;Oh SJ;Yoon MS;Jang SS;Holland RL;Reno ML;Hamad MN;Maeda T;Chung HJ;Chen J;Blanke SR
幽门螺杆菌（Hp）空泡细胞毒素（VacA）是一种进入宿主细胞并诱导线粒体功能障碍的细菌外毒素。然而，在何种程度上vaca依赖性线粒体扰动影响整体细胞代谢是知之甚少。我们报道线粒体中的VacA扰动与细胞氨基酸稳态的改变有关，这导致哺乳动物雷帕霉素靶蛋白复合物1 （mTORC1）的抑制和随后的自噬。mTORC1在营养胁迫期间调节细胞代谢，在Hp感染期间通过vaca依赖机制被抑制。这种vaca依赖性mTORC1信号的抑制与mTORC1从溶酶体表面解离有关，并通过Unc 51样激酶1 （Ulk1）复合物激活细胞自噬。VacA中毒导致细胞氨基酸减少，而增强的氨基酸池阻止VacA介导的mTORC1抑制。总之，这些研究支持Hp通过线粒体中VacA的作用调节宿主细胞代谢的模型。宿主代谢失调正成为微生物重塑感染微环境的重要策略。Kim等人报道了宿主营养状态的关键传感器mTORC1被一种靶向线粒体的细菌毒素幽门螺杆菌VacA抑制，导致细胞从生物合成向分解代谢的整体转变。
Helicobacter pylori (Hp) vacuolating cytotoxin (VacA) is a bacterial exotoxin that enters host cells and induces mitochondrial dysfunction. However, the extent to which VacA-dependent mitochondrial perturbations affect overall cellular metabolism is poorly understood. We report that VacA perturbations in mitochondria are linked to alterations in cellular amino acid homeostasis, which results in the inhibition of mammalian target of rapamycin complex 1 (mTORC1) and subsequent autophagy. mTORC1, which regulates cellular metabolism during nutrient stress, is inhibited during Hp infection by a VacA-dependent mechanism. This VacA-dependent inhibition of mTORC1 signaling is linked to the dissociation of mTORC1 from the lysosomal surface, and results in activation of cellular autophagy through the Unc 51-like kinase 1 (Ulk1) complex. VacA intoxication results in reduced cellular amino acids, and bolstering amino acid pools prevents VacA-mediated mTORC1 inhibition. Overall, these studies support a model that Hp modulate host cell metabolism through the action of VacA at mitochondria. Dysregulation of host metabolism is emerging as an important strategy for microbial remodeling of the infection microenvironment. Kim et al. report a key sensor of host nutritional status, mTORC1, is inhibited by a mitochondrial-targeting bacterial toxin, Helicobacter pylori VacA, resulting in an overall cellular shift from biosynthetic to catabolic metabolism.
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21.3
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影响因子：
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