Leishmania Repression of Host Translation through mTOR Cleavage Is Required for Parasite Survival and Infection
Leishmania Repression of Host Translation through mTOR Cleavage Is Required for Parasite Survival and Infection
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DOI：
10.1016/j.chom.2011.03.008
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发表时间：
2011-04-21
影响因子：
30.3
通讯作者：
Sonenberg, Nahum
中科院分区：
文献类型：
--
作者：
Jaramillo, Maritza;Gomez, Maria Adelaide;Sonenberg, Nahum
原生动物寄生虫利什曼原虫改变其宿主细胞巨噬细胞的活性。然而，人们对利什曼原虫感染对宿主蛋白质合成的影响知之甚少。在这里，我们发现利什曼原虫蛋白酶GP63切割雷帕霉素（mTOR）的哺乳动物/机制靶点，雷帕霉素是一种丝氨酸/苏氨酸激酶，调节翻译抑制因子4E-BP1。mTOR的切割导致mTOR复合物1 （mTORC1）的抑制和伴随的4E-BP1的激活，从而促进利什曼原虫的增殖。与这些结果一致的是，雷帕霉素对4e - bp的药理激活会导致寄生虫复制的急剧增加。相比之下，4E-BP1/2的基因缺失减少了巨噬细胞体内的寄生虫负荷，降低了体内对皮肤利什曼病的易感性。4E-BP1/2双敲除小鼠的寄生虫抗性表型涉及增强的I型IFN反应。本研究表明利什曼原虫通过激活4e - bp进化出一种生存机制，4e - bp是宿主翻译控制的主要靶点。
The protozoan parasite Leishmania alters the activity of its host cell, the macrophage. However, little is known about the effect of Leishmania infection on host protein synthesis. Here, we show that the Leishmania protease GP63 cleaves the mammalian/mechanistic target of rapamycin (mTOR), a serine/threonine kinase that regulates the translational repressor 4E-BP1. mTOR cleavage results in the inhibition of mTOR complex 1 (mTORC1) and concomitant activation of 4E-BP1 to promote Leishmania proliferation. Consistent with these results, pharmacological activation of 4E-BPs with rapamycin, results in a dramatic increase in parasite replication. In contrast, genetic deletion of 4E-BP1/2 reduces parasite load in macrophages ex vivo and decreases susceptibility to cutaneous leishmaniasis in vivo. The parasite resistant phenotype of 4E-BP1/2 double-knockout mice involves an enhanced type I IFN response. This study demonstrates that Leishmania evolved a survival mechanism by activating 4E-BPs, which serve as major targets for host translational control.