The virulence of Plasmodium falciparum , which causes the deadliest form of human malaria, is attributed to its ability to evade the human immune response. These parasites “choose” to express a single variant from a repertoire of surface antigens called PfEMP1, which are placed on the surface of the infected red cell. Immune evasion is achieved by switches in expression between var genes, each encoding a different Pf EMP1 variant. While the mechanisms that regulate mutually exclusive expression of var genes are still elusive, antisense long-noncoding RNAs (lncRNAs) transcribed from the intron of the active var gene were implicated in the “choice” of the single active var gene. Here, we show that this lncRNA colocalizes with the site of var mRNA transcription and is anchored to the var locus via DNA:RNA interactions. We define the var lncRNA interactome and identify a redox sensor, P. falciparum thioredoxin peroxidase I ( Pf TPx-1), as one of the proteins associated with the var antisense lncRNA. We show that Pf TPx-1 localizes to a nuclear subcompartment associated with active transcription on the nuclear periphery, in ring-stage parasite, when var transcription occurs. In addition, Pf TPx-1 colocalizes with S-adenosylmethionine synthetase ( Pf SAMS) in the nucleus, and its overexpression leads to activation of var2csa, similar to overexpression of Pf SAMS. Furthermore, we show that Pf TPx-1 knockdown alters the var switch rate as well as activation of additional gene subsets. Taken together, our data indicate that nuclear Pf TPx-1 plays a role in gene activation possibly by providing a redox-controlled nuclear microenvironment ideal for active transcription.

中文翻译：

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核氧化还原传感器调节恶性疟原虫的基因激活和变异转换

的毒力恶性疟原虫导致最致命形式的人类疟疾，归因于它逃避人类免疫反应的能力。这些寄生虫“选择”表达来自称为 PfEMP1 的表面抗原库的单一变体，这些抗原位于受感染的红细胞表面。免疫逃避是通过表达之间的转换来实现的变量基因，每个编码不同的PfEMP1 变体。虽然调节相互排斥表达的机制变量基因仍然难以捉摸，反义长链非编码 RNA (lncRNA) 从活性的内含子转录变量基因与单一活性的“选择”有关变量基因。在这里，我们表明该 lncRNA 与位点共定位变量mRNA 转录并锚定到变量通过 DNA 的基因座：RNA 相互作用。我们定义变量lncRNA 相互作用组并识别氧化还原传感器，恶性疟原虫硫氧还蛋白过氧化物酶 I (PfTPx-1），作为与变量反义 lncRNA。我们表明PfTPx-1 定位于与核周边活性转录相关的核亚区室，在环期寄生虫中，当变量转录发生。此外，PfTPx-1 与 S-腺苷甲硫氨酸合成酶共定位（PfSAMS）在细胞核中，其过度表达导致var2csa,类似于过度表达Pf萨姆斯。此外，我们表明PfTPx-1 击倒改变了变量转换率以及额外基因子集的激活。综上所述，我们的数据表明核PfTPx-1 可能通过提供一个氧化还原控制的核微环境来激活转录，从而在基因激活中发挥作用。