An exosome-based secretion pathway is responsible for protein export from Leishmania and communication with macrophages
An exosome-based secretion pathway is responsible for protein export from Leishmania and communication with macrophages
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DOI：
10.1242/jcs.056465
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发表时间：
2010-03-15
影响因子：
4
通讯作者：
Reiner, Neil E.
中科院分区：
文献类型：
--
作者：
Silverman, Judith Maxwell;Clos, Joachim;Reiner, Neil E.
许多细菌病原体使用专门的分泌系统将毒力因子输出到宿主目标细胞中。利什曼原虫和其他真核细胞内病原体也将效应蛋白运送到宿主细胞；然而，涉及的机制仍然不清楚。在这份报告中，我们确认外切体分泌是利什曼原虫蛋白分泌的一般机制，并表明外切体参与了蛋白质向宿主靶细胞的输送。比较定量蛋白质组学明确地确定了利什曼原虫外体中的329种蛋白质，占这些生物全球蛋白质分泌量的52%。我们的发现表明，感染类应激源(37℃/-pH 5.5)上调外切体的释放，使外切体的蛋白组成增加一倍以上。在感染的巨噬细胞胞浆中检测到利什曼原虫外切体和外切体蛋白，并选择性地诱导巨噬细胞分泌IL-8，而不是分泌肿瘤坏死因子-α。因此，我们为利什曼原虫输出蛋白质的一种明显广泛的机制提供了证据。此外，我们描述了利什曼原虫分子直接输送到巨噬细胞的机制。这些发现表明，利什曼原虫外切体和哺乳动物外切体一样，在远程交流和免疫调节中发挥作用。
Specialized secretion systems are used by numerous bacterial pathogens to export virulence factors into host target cells. Leishmania and other eukaryotic intracellular pathogens also deliver effector proteins into host cells; however, the mechanisms involved have remained elusive. In this report, we identify exosome-based secretion as a general mechanism for protein secretion by Leishmania, and show that exosomes are involved in the delivery of proteins into host target cells. Comparative quantitative proteomics unambiguously identified 329 proteins in Leishmania exosomes, accounting for >52% of global protein secretion from these organisms. Our findings demonstrate that infection-like stressors (37 degrees C +/- pH 5.5) upregulated exosome release more than twofold and also modified exosome protein composition. Leishmania exosomes and exosomal proteins were detected in the cytosolic compartment of infected macrophages and incubation of macrophages with exosomes selectively induced secretion of IL-8, but not TNF-alpha. We thus provide evidence for an apparently broad-based mechanism of protein export by Leishmania. Moreover, we describe a mechanism for the direct delivery of Leishmania molecules into macrophages. These findings suggest that, like mammalian exosomes, Leishmania exosomes function in long-range communication and immune modulation.