Sir2 paralogues cooperate to regulate virulence genes and antigenic variation in Plasmodium falciparum.
Sir2 paralogues cooperate to regulate virulence genes and antigenic variation in Plasmodium falciparum.
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DOI：
10.1371/journal.pbio.1000084
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发表时间：
2009-04-14
期刊：
影响因子：
9.8
通讯作者：
Cowman AF
中科院分区：
文献类型：
--
作者：
Tonkin CJ;Carret CK;Duraisingh MT;Voss TS;Ralph SA;Hommel M;Duffy MF;Silva LM;Scherf A;Ivens A;Speed TP;Beeson JG;Cowman AF
恶性疟原虫感染的红细胞在脑、器官和外周微血管中的细胞粘附与严重疟疾相关的发病率和死亡率有关。寄生虫来源的恶性疟原虫红细胞膜蛋白1（PfEMP 1）分子显示在红细胞表面上，负责细胞粘附并在感染过程中经历抗原变异。PfEMP 1的抗原变异是通过var基因家族的原位转换和互斥转录实现的，这是一个受表观遗传机制控制的过程。在这里，我们报告的恶性疟原虫沉默的信息调节器的A和B（PfSir2A和PfSir2 B）和它们的相互排斥和沉默的var基因库的参与表征。对缺乏PfSir2A或PfSir2B的恶性疟原虫的分析表明，这些NAD+依赖性组蛋白脱乙酰酶是沉默根据其保守启动子类型分类的不同var基因子集所必需的。我们还证明，在没有这些分子的情况下，相互排斥的var基因表达崩溃。我们发现，var基因沉默起源于启动子和PfSir2旁系同源物参与顺式传播沉默的染色质到相邻区域。此外，缺乏PfSir2A而不是PfSir2B的寄生虫具有相当长的端粒重复序列，证明了该分子在端粒末端保护中的作用。这项工作强调了PfSir2旁系同源物在恶性疟原虫毒力基因的表观遗传沉默和疟疾感染致病性控制中的关键但独特的作用。单细胞寄生虫恶性疟原虫是最严重的疟疾的病因，每年造成3亿人感染和1200万人死亡。受感染的红细胞聚集并阻塞外周循环、脑和胎盘中的毛细血管，是疟疾病理学的主要贡献者。寄生虫衍生的蛋白质显示在受感染的红细胞表面，是红细胞聚集在毛细血管中的原因。虽然60个亚端粒变异基因可以编码这种“粘性”毛细血管结合蛋白的不同版本，但一次只能表达一种蛋白质，这些基因之间的表达转换会导致这种致病分子的变异，使寄生虫能够逃避免疫系统。在这里，我们确定了两个染色质修饰蛋白，合作介导沉默和相互排斥的var基因的表达。因此，这些蛋白质是引起疟疾的寄生虫的重要毒力因子。对引起疟疾的寄生虫中的两种Sir 2组蛋白脱乙酰酶的研究表明，反式作用的表观遗传因子控制着主要亚端粒毒力基因家族的互斥表达。
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. 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.
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82.9
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64.8
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Carlton, Jane M.;Adams, John H.;Silva, Joana C.;Bidwell, Shelby L.;Lorenzi, Hernan;Caler, Elisabet;Crabtree, Jonathan;Angiuoli, Samuel V.;Merino, Emilio F.;Amedeo, Paolo;Cheng, Qin;Coulson, Richard M. R.;Crabb, Brendan S.;del Portillo, Hernando A.;Essien, Kobby;Feldblyum, Tamara V.;Fernandez-Becerra, Carmen;Gilson, Paul R.;Gueye, Amy H.;Guo, Xiang;Kang'a, Simon;Kooij, Taco W. A.;Korsinczky, Michael;Meyer, Esmeralda V. -S.;Nene, Vish;Paulsen, Ian;White, Owen;Ralph, Stuart A.;Ren, Qinghu;Sargeant, Tobias J.;Salzberg, Steven L.;Stoeckert, Christian J.;Sullivan, Steven A.;Yamamoto, Marcio M.;Hoffman, Stephen L.;Wortman, Jennifer R.;Gardner, Malcolm J.;Galinski, Mary R.;Barnwell, John W.;Fraser-Liggett, Claire M.
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Fraser-Liggett, Claire M.
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6.7
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Cortés A;Carret C;Kaneko O;Yim Lim BY;Ivens A;Holder AA
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Holder AA
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12.3
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Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
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Zhang J
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