Immune evasion by Plasmodium falciparum involves differential expression of var genes, which encode members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family that are expressed on the surface of infected erythrocytes; however, the mechanistic basis of antigenic variation is poorly understood. Now, Scherf and colleagues identify a novel exoribonuclease that silences the expression of var gene transcripts, which are involved in the pathogenesis of severe malaria.

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P. falciparum usuallyexpresses only one var gene variant at a time (known as monoallelic expression), and the upsA subgroup in particular is associated with severe malaria. Apart from histone modifications, other potential post-transcriptional mechanisms that control antigenic variation are understudied, which led the authors to examine whether RNA-based regulation might occur. Bioinformatic analysis of the P. falciparum genome identified a non-canonical exoribonuclease that contains a putative RNase II domain (termed PfRNase II), and immunoelectron microscopy, in combination with RNA degradation experiments, showed that it localizes to the nucleus and degrades single-stranded RNA. Collectively, these data suggest that PfRNase II has a potential role in mediating the decay of mRNAs.

But does PfRNase II target var gene transcripts? RNA sequencing analysis of total RNA revealed that, compared with wild-type parasites, upsA genes were strongly upregulated in parasites that expressed a defective PfRNase II. Furthermore, real-time quantitative PCR (qPCR) showed that different combinations of up to three distinct upsA genes, together with a upsC gene, were upregulated simultaneously in single parasite clones, which indicates that loss of PfRNase II activity abolishes monoallelic var gene expression and induces the switching of upsA genes. Chromatin immunoprecipitation (ChIP)–qPCR confirmed that PfRNase II is enriched at the promoters and introns of silenced upsA transcripts, and transcription analysis revealed that the nascent transcripts are only short-lived, cryptic mRNAs. Finally, the authors demonstrated that PfRNase II activity is clinically relevant, as parasites from patients with severe malaria showed an inverse correlation between the levels of PfRNase II and upsA mRNAs.

a novel exonuclease that promotes monoallelic var gene expression in malaria parasites

This study identifies a novel exoribonuclease that promotes monoallelic var gene expression in malaria parasites. It will be interesting to see whether this mechanism is a widespread phenomenon for the control of antigenic variation in Plasmodium spp.