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Exonuclease-mediated degradation of nascent RNA silences genes linked to severe malaria.
- Source :
-
Nature [Nature] 2014 Sep 18; Vol. 513 (7518), pp. 431-5. Date of Electronic Publication: 2014 Jun 29. - Publication Year :
- 2014
-
Abstract
- Antigenic variation of the Plasmodium falciparum multicopy var gene family enables parasite evasion of immune destruction by host antibodies. 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. 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 virulence genes involved in pathogenesis in patients with severe malaria may provide new strategies for reducing malaria mortality.
- Subjects :
- Alleles
Antigenic Variation genetics
Chromatin enzymology
Down-Regulation genetics
Erythrocytes parasitology
Exoribonucleases deficiency
Exoribonucleases genetics
Humans
Introns genetics
Malaria, Falciparum parasitology
Plasmodium falciparum pathogenicity
Promoter Regions, Genetic genetics
Protozoan Proteins genetics
RNA, Messenger genetics
RNA, Messenger metabolism
RNA, Protozoan genetics
RNA, Untranslated genetics
RNA, Untranslated metabolism
Transcription Initiation Site
Virulence genetics
Virulence Factors genetics
Exoribonucleases metabolism
Gene Silencing
Genes, Protozoan genetics
Malaria, Cerebral parasitology
Plasmodium falciparum enzymology
Plasmodium falciparum genetics
RNA, Protozoan metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 513
- Issue :
- 7518
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 25043062
- Full Text :
- https://doi.org/10.1038/nature13468