title: Exonuclease-mediated degradation of nascent RNA silences genes linked to severe malaria.
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.
authors.affiliation: 1] Research Center for Translational Medicine, Shanghai East Hospital and Institute of Infectious Diseases and Vaccine Development, Tongji University School of Medicine, Shanghai 200120, China [2] Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris, France [3] CNRS, URA 2581, F-75724 Paris, France.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 1] Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris, France [2] CNRS, URA 2581, F-75724 Paris, France [3] Research Center for Infectious Diseases, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: T Nicolai
authors.initials: TN
authors.lastname: Siegel
authors.affiliation: 1] Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris, France [2] CNRS, URA 2581, F-75724 Paris, France.
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Martins
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital and Institute of Infectious Diseases and Vaccine Development, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Jiangsu Institute of Parasitic Diseases, Key Laboratory of Parasitic Disease Control and Prevention (Ministry of Health), and Jiangsu Provincial Key Laboratory of Parasite Molecular Biology, Wuxi 214064, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
authors.affiliation: Jiangsu Institute of Parasitic Diseases, Key Laboratory of Parasitic Disease Control and Prevention (Ministry of Health), and Jiangsu Provincial Key Laboratory of Parasite Molecular Biology, Wuxi 214064, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiu
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lubin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Cell Biology of Parasitism Unit, Institut Pasteur, and INSERM U786, F-75724 Paris, France.
authors.forename: Chung-Chau
authors.initials: CC
authors.lastname: Hon
authors.affiliation: 1] Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris, France [2] CNRS, URA 2581, F-75724 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Scheidig-Benatar
authors.affiliation: 1] Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris, France [2] CNRS, URA 2581, F-75724 Paris, France.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology &Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology &Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Anja T R
authors.initials: AT
authors.lastname: Jensen
authors.affiliation: 1] Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris, France [2] CNRS, URA 2581, F-75724 Paris, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Claes
authors.affiliation: 1] Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris, France [2] CNRS, URA 2581, F-75724 Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Guizetti
authors.affiliation: 1] Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris, France [2] CNRS, URA 2581, F-75724 Paris, France.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Malmquist
authors.affiliation: 1] Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris, France [2] CNRS, URA 2581, F-75724 Paris, France.
authors.forename: Artur
authors.initials: A
authors.lastname: Scherf
mesh_terms: D000483:Alleles; D000940:Antigenic Variation / Q000235:genetics; D002843:Chromatin / Q000201:enzymology; D015536:Down-Regulation / Q000235:genetics; D004912:Erythrocytes / Q000469:parasitology; D005095:Exoribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D017125:Genes, Protozoan / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D016779:Malaria, Cerebral / Q000469:parasitology*; D016778:Malaria, Falciparum / Q000469:parasitology; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics* / Q000472:pathogenicity; D011401:Promoter Regions, Genetic / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016053:RNA, Protozoan / Q000235:genetics / Q000378:metabolism*; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D024363:Transcription Initiation Site; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics
chemical_list: D002843:Chromatin; D015800:Protozoan Proteins; D012333:RNA, Messenger; D016053:RNA, Protozoan; D022661:RNA, Untranslated; D037521:Virulence Factors; D005095:Exoribonucleases; C022535:exoribonuclease II