Strain-specific disruption of interferon-stimulated N-myc and STAT interactor (NMI) function by Toxoplasma gondii type I ROP18 in human cells
Strain-specific disruption of interferon-stimulated N-myc and STAT interactor (NMI) function by Toxoplasma gondii type I ROP18 in human cells
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DOI：
10.1017/s0031182020001249
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发表时间：
2020-07
期刊：
影响因子：
2.4
通讯作者：
Jing Xia;M. Blank;Lijuan Zhou;Shuizhen Wu;Hong-Juan Peng;J. Boyle
中科院分区：
文献类型：
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作者：
Jing Xia;M. Blank;Lijuan Zhou;Shuizhen Wu;Hong-Juan Peng;J. Boyle
摘要弓形虫棒状体蛋白TgROP 18是一种靶向免疫相关GTP酶的多态性毒力效应蛋白。鉴于IRG在啮齿类动物中是唯一多样化的，而在其他T。在弓形虫中间宿主中，TgROP 18在操纵非啮齿动物细胞中的作用尚不清楚。在这里，我们表明，在人类细胞中TgROP 18 I相互作用的干扰素-γ-诱导蛋白N-myc和STAT相互作用（NMI），这是一个属性，是唯一的I型TgROP 18等位基因。具体地，当在哺乳动物细胞中异位表达时，在IFN-γ处理的细胞中，仅TgROP 18 I与匪I共免疫沉淀，而TgROP 18 II则不。在表达TgROP 18 I或TgROP 18 II的寄生虫中，NMI仅与TgROP 18 I共免疫沉淀，这与NMI在寄生虫空泡膜（PVM）上的等位基因特异性免疫定位有关。我们还发现TgROP 18 I减少了NMI与IRF 1基因启动子中IFN-γ激活序列（GAS）的结合。最后，我们确定TgROP 18 I的C-末端激酶结构域中的多态性是对NMI的等位基因特异性效应所必需的。总之，这些数据进一步定义了TgROP 18 I靶向的新宿主途径，并提供了由高度多态性ROP 18基因座中的等位基因差异驱动的第一个功能。
Abstract Toxoplasma gondii rhoptry protein TgROP18 is a polymorphic virulence effector that targets immunity-related GTPases (IRGs) in rodents. Given that IRGs are uniquely diversified in rodents and not in other T. gondii intermediate hosts, the role of TgROP18 in manipulating non-rodent cells is unclear. Here we show that in human cells TgROP18I interacts with the interferon-gamma-inducible protein N-myc and STAT interactor (NMI) and that this is a property that is unique to the type I TgROP18 allele. Specifically, when expressed ectopically in mammalian cells only TgROP18I co-immunoprecipitates with NMI in IFN-γ-treated cells, while TgROP18II does not. In parasites expressing TgROP18I or TgROP18II, NMI only co-immunoprecipitates with TgROP18I and this is associated with allele-specific immunolocalization of NMI on the parasitophorous vacuolar membrane (PVM). We also found that TgROP18I reduces NMI association with IFN-γ-activated sequences (GAS) in the IRF1 gene promoter. Finally, we determined that polymorphisms in the C-terminal kinase domain of TgROP18I are required for allele-specific effects on NMI. Together, these data further define new host pathway targeted by TgROP18I and provide the first function driven by allelic differences in the highly polymorphic ROP18 locus.