Institute of Infectious Diseases and Vaccine Development, Tongji University School of Medicine, Shanghai, China.
Cell Host Microbe. 2011 Nov 17;10(5):451-63. doi: 10.1016/j.chom.2011.09.013.
Many microbial pathogens, including the malaria parasite Plasmodium falciparum, vary surface protein expression to evade host immune responses. P. falciparium antigenic variation is linked to var gene family-encoded clonally variant surface protein expression. Mututally exclusive var gene expression is partially controlled by spatial positioning; silent genes are retained at distinct perinuclear sites and relocated to transcriptionally active locations for monoallelic expression. We show that var introns can control this process and that var intron addition relocalizes episomes from a random to a perinuclear position. This var intron-regulated nuclear tethering and repositioning is linked to an 18 bp nuclear protein-binding element that recruits an actin protein complex. Pharmacologically induced F-actin formation, which is restricted to the nuclear periphery, repositions intron-carrying episomes and var genes and disrupts mutually exclusive var gene expression. Thus, actin polymerization relocates var genes from a repressive to an active perinuclear compartment, which is crucial for P. falciparium phenotypic variation and pathogenesis.
许多微生物病原体，包括疟原虫 Plasmodium falciparum，都会改变表面蛋白表达来逃避宿主免疫反应。疟原虫抗原变异与 var 基因家族编码的克隆变异表面蛋白表达有关。相互排斥的 var 基因表达部分受空间定位控制；沉默基因保留在特定的核周位置，并重新定位到转录活跃的位置进行单等位基因表达。我们表明 var 内含子可以控制这个过程，并且 var 内含子的添加将外显子从随机位置重新定位到核周位置。这种 var 内含子调控的核固定和重新定位与一个 18 个碱基对的核蛋白结合元件有关，该元件募集一个肌动蛋白蛋白复合物。药理学诱导的 F-肌动蛋白形成仅限于核周，重新定位携带内含子的外显子和 var 基因，并破坏相互排斥的 var 基因表达。因此，肌动蛋白聚合将 var 基因从抑制性的核周隔室重新定位到活性的核周隔室，这对于疟原虫表型变异和发病机制至关重要。
