Leishmania parasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine in Leishmania infections.
Leishmania parasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine in Leishmania infections.
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利什曼原虫寄生液泡膜展示磷酸肌醇，为持续激活 Akt 创造条件，并成为利什曼原虫感染中米替福辛的靶标。
DOI：
10.1111/cmi.12889
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发表时间：
2018
影响因子：
3.4
通讯作者：
Kima,PeterE
中科院分区：
文献类型：
--
作者：
Zhang,Naixin;Prasad,Samiksha;HuyghuesDespointes,Charles-Eugene;Young,Jeffrey;Kima,PeterE
米替福新是治疗利什曼病的重要药物，但其作用机制仍知之甚少。在这些研究中，我们测试了这样的假设，即像在癌细胞中一样，米替福新在利什曼病中的功效是由于其抑制宿主细胞中的Akt活化。我们显示使用通过不同机制阻断Akt激活的药理学药物，并且还使用诱导性敲低方法，当米替福新与Akt1的接触受限时，米替福新失去其功效。有趣的是，Akt激活的限制导致了已建立的利什曼原虫感染的清除。然后，我们使用荧光标记的探针结合磷酸肌醇，利什曼原虫空泡膜（LPVM）显示相关的磷酸肌醇，Akt可以被招募并持续激活。综上所述，我们认为PI（4）P的获得和PI（3，4）P2在LPVM上的展示启动了支持持续Akt激活和对米替福新敏感性的机制。
Miltefosine is an important drug for the treatment of leishmaniasis; however, its mechanism of action is still poorly understood. In these studies, we tested the hypothesis that like in cancer cells, miltefosine's efficacy in leishmaniasis is due to its inhibition of Akt activation in host cells. We show using pharmacologic agents that block Akt activation by different mechanisms and also using an inducible knockdown approach that miltefosine loses its efficacy when its access to Akt1 is limited. Interestingly, limitation of Akt activation results in clearance of establishedLeishmaniainfections. We then show, using fluorophore‐tagged probes that bind to phosphoinositides, thatLeishmaniaparasitophorous vacuole membranes (LPVMs) display the relevant phosphoinositides to which Akt can be recruited and activated continuously. Taken together, we propose that the acquisition of PI(4) P and the display of PI (3,4)P2 on LPVMs initiate the machinery that supports continuous Akt activation and sensitivity to miltefosine.