A Mycobacterium tuberculosis effector targets mitochondrion, controls energy metabolism and limits cytochrome c exit
A Mycobacterium tuberculosis effector targets mitochondrion, controls energy metabolism and limits cytochrome c exit
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结核分枝杆菌效应子以线粒体为目标，控制能量代谢并限制细胞色素 c 的退出
DOI：
10.1101/2021.01.31.428746
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Martin M
中科院分区：
文献类型：
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作者：
Martin M
宿主代谢重编程是结核分枝杆菌（Mtb）感染的关键特征，其使得该病原体能够在吞噬细胞内存活并调节促进结核病传播的免疫应答。在这里，我们表明，以前未表征的分泌蛋白从结核分枝杆菌，Rv1813c，操纵宿主代谢靶向线粒体。当在真核细胞中表达时，该蛋白被递送到线粒体膜间隙，并通过促进氧化磷酸化代谢途径来促进宿主ATP产生的增强。此外，细胞色素从线粒体的释放，响应于短期氧化应激的早期凋亡事件，在Rv1813c表达细胞中被延迟。这项研究揭示了一类新的线粒体靶向效应器从Mtbthat可能参与宿主细胞代谢重编程和凋亡控制duringMtbinfections.IMPORTANCEIn这篇文章中，使用相结合的技术（生物信息学，结构生物学和细胞生物学），我们确定和特点的一类新的效应器只存在于细胞内分枝杆菌。这些蛋白质在细胞中异位表达时特异性靶向宿主细胞线粒体。我们发现，这个家族的一个成员（Rv1813c）以一种可能扭曲免疫反应的方式影响线粒体代谢。这种效应物还抑制线粒体的细胞色素退出，表明它可能改变正常宿主细胞的凋亡能力，这是免疫细胞对抗Mt感染的第一道防线之一。
Host metabolism reprogramming is a key feature of Mycobacterium tuberculosis (Mtb) infection that enables the survival of this pathogen within phagocytic cells and modulates the immune response facilitating the spread of the tuberculosis disease. Here, we demonstrate that a previously uncharacterized secreted protein fromMtb, Rv1813c, manipulates the host metabolism by targeting mitochondria. When expressed in eukaryotic cells, the protein is delivered to the mitochondrial intermembrane space and promotes the enhancement of host ATP production by boosting the oxidative phosphorylation metabolic pathway. Furthermore, the release of cytochromecfrom mitochondria, an early apoptotic event in response to short-term oxidative stress, is delayed in Rv1813c-expressing cells. This study reveals a novel class of mitochondria targeting effectors fromMtbthat might participate in host cell metabolic reprogramming and apoptosis control duringMtbinfections.IMPORTANCEIn this article, using a combination of techniques (bioinformatics, structural biology, and cell biology), we identified and characterized a new class of effectors present only in intracellular mycobacteria. These proteins specifically target host cell mitochondria when ectopically expressed in cells. We showed that one member of this family (Rv1813c) affects mitochondria metabolism in a way that might twist the immune response. This effector also inhibits the cytochromecexit from mitochondria, suggesting that it might alter normal host cell apoptotic capacities, one of the first defenses of immune cells againstMtbinfection.