A nuclear redox sensor modulates gene activation and <i>var</i> switching in <i>Plasmodium falciparum</i>.

Abstract

The virulence of <i>Plasmodium falciparum</i>, 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 <i>var</i> genes, each encoding a different <i>Pf</i>EMP1 variant. While the mechanisms that regulate mutually exclusive expression of <i>var</i> genes are still elusive, antisense long-noncoding RNAs (lncRNAs) transcribed from the intron of the active <i>var</i> gene were implicated in the "choice" of the single active <i>var</i> gene. Here, we show that this lncRNA colocalizes with the site of <i>var</i> mRNA transcription and is anchored to the <i>var</i> locus via DNA:RNA interactions. We define the <i>var</i> lncRNA interactome and identify a redox sensor, <i>P. falciparum</i> thioredoxin peroxidase I (<i>Pf</i>TPx-1), as one of the proteins associated with the <i>var</i> antisense lncRNA. We show that <i>Pf</i>TPx-1 localizes to a nuclear subcompartment associated with active transcription on the nuclear periphery, in ring-stage parasite, when <i>var</i> transcription occurs. In addition, <i>Pf</i>TPx-1 colocalizes with S-adenosylmethionine synthetase (<i>Pf</i>SAMS) in the nucleus, and its overexpression leads to activation of <i>var2csa,</i> similar to overexpression of <i>Pf</i>SAMS. Furthermore, we show that <i>Pf</i>TPx-1 knockdown alters the <i>var</i> switch rate as well as activation of additional gene subsets. Taken together, our data indicate that nuclear <i>Pf</i>TPx-1 plays a role in gene activation possibly by providing a redox-controlled nuclear microenvironment ideal for active transcription.