Manipulation of the host cell is a crucial part of life for many intracellular organisms. We have recently come to appreciate the extent to which the intracellular pathogen Toxoplasma gondii reprograms its host cell, and this is illustrated by the marked upregulation of the central regulator c-Myc, an oncogene that coordinates myriad cellular functions. In an effort to identify an effector protein capable of regulating c-Myc, our laboratory constructed a screen for mutant parasites unable to accomplish this upregulation. Interestingly, this screen identified numerous components of a complex located in/on the parasitophorous vacuole membrane necessary to translocate Toxoplasma proteins out into the host cytosol, but it never identified a specific effector protein. Thus, how the parasite upregulates c-Myc has largely been a mystery. Previously, the Toxoplasma dense granule protein GRA16 has been described to bind to one isoform of PP2A-B, a regulatory subunit that coordinates the activity of the catalytic protein phosphatase PP2A. As other PP2A subunits have been reported to target PP2A protein phosphatase activity to c-Myc, subsequently leading to c-Myc destabilization, we examined whether GRA16 has an impact on host c-Myc accumulation. Expression of Toxoplasma’s GRA16 protein in Neospora caninum, a close relative of Toxoplasma that does not naturally upregulate host c-Myc, conferred the ability on Neospora to do this now. Further support was obtained by deleting the GRA16 gene from Toxoplasma and observing a severely diminished ability of Toxoplasma tachyzoites to upregulate host c-Myc. Thus, GRA16 is an effector protein central to Toxoplasma’s ability to upregulate host c-Myc.

中文翻译：

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弓形虫利用 GRA16 上调宿主 c-Myc。


操纵宿主细胞是许多细胞内生物生命的重要组成部分。我们最近开始认识到细胞内病原体弓形虫对其宿主细胞进行重新编程的程度，这可以通过中央调节因子 c-Myc 的显着上调来说明，c-Myc 是一种协调多种细胞功能的癌基因。为了鉴定能够调节 c-Myc 的效应蛋白，我们的实验室构建了无法实现这种上调的突变寄生虫的筛选。有趣的是，该筛选鉴定了位于寄生液泡膜内/上的复合物的许多成分，该复合物是将弓形虫蛋白转移到宿主细胞质中所必需的，但它从未鉴定出特定的效应蛋白。因此，寄生虫如何上调 c-Myc 在很大程度上一直是个谜。此前，弓形虫致密颗粒蛋白 GRA16 已被描述为与 PP2A-B 的一种亚型结合，PP2A-B 是协调催化蛋白磷酸酶 PP2A 活性的调节亚基。据报道，其他 PP2A 亚基可将 PP2A 蛋白磷酸酶活性靶向 c-Myc，随后导致 c-Myc 不稳定，因此我们检查了 GRA16 是否对宿主 c-Myc 积累有影响。弓形虫的 GRA16 蛋白在犬新孢子虫（弓形虫的近亲）中的表达赋予了新孢子虫现在这样做的能力，它不会自然地上调宿主 c-Myc。通过从弓形虫中删除GRA16基因并观察到弓形虫速殖子上调宿主 c-Myc 的能力严重减弱，获得了进一步的支持。 因此，GRA16 是弓形虫上调宿主 c-Myc 能力的核心效应蛋白。