Exonuclease-mediated degradation of nascent RNA silences genes linked to severe malaria

A novel type of post-transcriptional regulation controls the expression of virulence genes in blood-stage malaria parasites. Gene silencing by malaria parasites The malaria parasite, Plasmodium falciparum , evades the host immune system through antigenic variation controlled by the var gene family. The upsA var subgroup is linked with pathogenesis of cerebral malaria, but the mechanisms underlying its activation are unclear. This paper reports the identification of a novel chromatin-associated exoribonuclease, PfRNase II, and reveals exonuclease-mediated degradation of nascent upsA mRNA as a new type of gene silencing mechanism important for antigenic variation and cerebral malaria. The identification of a Plasmodium protein controlling virulence factors expressed in patients with a severe form of malaria may provide potential targets for antimalarial therapy. Antigenic variation of the Plasmodium falciparum multicopy var gene family enables parasite evasion of immune destruction by host antibodies 1 , 2 . Expression of a particular var subgroup, termed upsA , is linked to the obstruction of blood vessels in the brain and to the pathogenesis of human cerebral malaria 3 , 4 , 5 , 6 . The mechanism determining upsA activation remains unknown. Here we show that an entirely new type of gene silencing mechanism involving an exonuclease-mediated degradation of nascent RNA controls the silencing of genes linked to severe malaria. We identify a novel chromatin-associated exoribonuclease, termed PfRNase II, that controls the silencing of upsA var genes by marking their transcription start site and intron-promoter regions leading to short-lived cryptic RNA. Parasites carrying a deficient PfRNase II gene produce full-length upsA var transcripts and intron-derived antisense long non-coding RNA. The presence of stable upsA var transcripts overcomes monoallelic expression, resulting in the simultaneous expression of both upsA and upsC type PfEMP1 proteins on the surface of individual infected red blood cells. In addition, we observe an inverse relationship between transcript levels of PfRNase II and upsA -type var genes in parasites from severe malaria patients, implying a crucial role of PfRNase II in severe malaria. Our results uncover a previously unknown type of post-transcriptional gene silencing mechanism in malaria parasites with repercussions for other organisms. Additionally, the identification of RNase II as a parasite protein controlling the expression of vir