Sir2 paralogues cooperate to regulate virulence genes and antigenic variation in Plasmodium falciparum
| Autor: | Manoj T. Duraisingh, Liliana Mancio da Silva, Terence P. Speed, Artur Scherf, Mirja Hommel, Michael F. Duffy, Alasdair Ivens, Christopher J. Tonkin, Celine Carret, Alan F. Cowman, James G. Beeson, Till S. Voss, Stuart A. Ralph |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Transcriptional Activation
Erythrocytes QH301-705.5 Plasmodium falciparum Protozoan Proteins Antigens Protozoan Biology Microbiology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Gene expression parasitic diseases Antigenic variation Cell Adhesion Gene family Gene silencing Animals Humans Sirtuins Epigenetics Gene Silencing Biology (General) Malaria Falciparum Promoter Regions Genetic Gene Molecular Biology 030304 developmental biology Genetics 0303 health sciences General Immunology and Microbiology Virulence 030306 microbiology General Neuroscience Membrane Proteins Genetics and Genomics Telomere biology.organism_classification Antigenic Variation 3. Good health Chromatin Infectious Diseases General Agricultural and Biological Sciences Research Article |
| Zdroj: | Tonkin, C J, Carret, C K, Duraisingh, M T, Voss, T S, Ralph, S A, Hommel, M, Duffy, M F, Silva, L M D, Scherf, A, Ivens, A, Speed, T P, Beeson, J G & Cowman, A F 2009, ' Sir2 paralogues cooperate to regulate virulence genes and antigenic variation in Plasmodium falciparum ', PLoS Biology, vol. 7, no. 4, e1000084, pp. 1-18 . https://doi.org/10.1371/journal.pbio.1000084 PLoS Biology PLoS Biology, Vol 7, Iss 4, p e84 (2009) |
| DOI: | 10.1371/journal.pbio.1000084 |
| Popis: | Cytoadherance of Plasmodium falciparum-infected erythrocytes in the brain, organs and peripheral microvasculature is linked to morbidity and mortality associated with severe malaria. Parasite-derived P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) molecules displayed on the erythrocyte surface are responsible for cytoadherance and undergo antigenic variation in the course of an infection. Antigenic variation of PfEMP1 is achieved by in situ switching and mutually exclusive transcription of the var gene family, a process that is controlled by epigenetic mechanisms. Here we report characterisation of the P. falciparum silent information regulator's A and B (PfSir2A and PfSir2B) and their involvement in mutual exclusion and silencing of the var gene repertoire. Analysis of P. falciparum parasites lacking either PfSir2A or PfSir2B shows that these NAD+-dependent histone deacetylases are required for silencing of different var gene subsets classified by their conserved promoter type. We also demonstrate that in the absence of either of these molecules mutually exclusive expression of var genes breaks down. We show that var gene silencing originates within the promoter and PfSir2 paralogues are involved in cis spreading of silenced chromatin into adjacent regions. Furthermore, parasites lacking PfSir2A but not PfSir2B have considerably longer telomeric repeats, demonstrating a role for this molecule in telomeric end protection. This work highlights the pivotal but distinct role for both PfSir2 paralogues in epigenetic silencing of P. falciparum virulence genes and the control of pathogenicity of malaria infection. Author Summary The unicellular parasite Plasmodium falciparum is the cause of the most severe form of malaria and is responsible for 300 million infections and ∼2 million deaths a year. Infected erythrocytes clump and block capillaries in the peripheral circulation, the brain, and placenta and are a major contributor to the pathology of malaria. A parasite-derived protein displayed on the surface of the infected erythrocyte is responsible for erythrocyte clumping in capillaries. Although 60 subtelomeric var genes can encode different versions of this “sticky” capillary-binding protein, only one protein is expressed at a time, and switches in expression between these genes causes variation of this pathogenic molecule enabling the parasite to evade the immune system. Here we identify two chromatin-modifying proteins that cooperate to mediate silencing and mutual exclusive expression of var genes. These proteins are thus important virulence factors of the malaria-causing parasite. Investigation into two Sir2 histone deacetylases in the malaria-causing parasite revealstrans-acting epigenetic factors control mutually exclusive expression of a major subtelomeric virulence gene family. |
| Databáze: | OpenAIRE |
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