Expression site attenuation mechanistically links antigenic variation and development in Trypanosoma brucei.
Expression site attenuation mechanistically links antigenic variation and development in Trypanosoma brucei.
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DOI：
10.7554/elife.02324
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发表时间：
2014-05-20
期刊：
影响因子：
7.7
通讯作者：
Engstler M
中科院分区：
文献类型：
--
作者：
Batram C;Jones NG;Janzen CJ;Markert SM;Engstler M
我们发现了一种新的单等位基因表达机制，它将模型寄生虫布鲁氏锥虫的抗原变异、细胞周期和发育联系起来。非洲锥虫具有数百个不同的表面糖蛋白（VSG）基因，但在任何给定时间只有一个基因从端粒表达位点（ES）表达。我们发现，单独表达第二个VSG足以沉默活性VSG基因，并通过端粒沉默- 1b （DOT1B）介导的组蛋白甲基化干扰物定向减弱ES。三个保守的表达位点相关基因（esag）似乎是ES衰减的信号。它们的耗尽导致g1期休眠，并可逆地启动细长到矮秆的分化途径。经es减毒的细长血流锥虫获得了向采采蝇阶段转化的完全发育能力。抗原变异和发育进程之间的这种令人惊讶的联系为对抗致命的昏睡病提供了一个意想不到的切入点。非洲昏睡病是一种潜在的致命疾病，由一种叫做布氏t虫的寄生虫引起，并通过采采蝇传播。像许多引起热带疾病的寄生虫一样，布鲁氏疟原虫利用遗传欺骗来逃避人类和其他哺乳动物的免疫系统。这包括定期改变寄生虫周围的变异表面糖蛋白（VSG）外壳，以保持比宿主的免疫系统领先一步：当免疫系统寻找穿着特定外壳的入侵者时，寄生虫正在以完全不同的外壳在宿主中传播。为了感染其他宿主，寄生虫必须经历变化，使其能够再次感染采采蝇。因此，除了“抗原性变异”允许它在宿主血液中改变其表面外壳外，布氏体在能够殖民采采蝇之前必须经历更基本的蜕变。然而，允许寄生虫重新感染苍蝇的许多变化细节尚不清楚。布氏体有几百个VSG基因聚集在大约15个被称为表达位点的区域，但在任何给定的时间只有一个表达位点是活跃的。每个表达位点还包含许多其他基因，称为表达位点相关基因（esag）。抗原变异可能是同一表达位点内的不同VSG基因作为蛋白质表达的结果，或者是活性表达位点沉默而另一个表达位点被激活的结果。这是另一个尚未完全了解的过程。Batram等人现在发现VSG基因的表达、抗原变异和允许寄生虫重新感染果蝇的变化都是相互关联的。这表明，该表达位点可以为抗击非洲昏睡病提供一个新的切入点。DOI: http://dx.doi.org/10.7554/eLife.02324.002
We have discovered a new mechanism of monoallelic gene expression that links antigenic variation, cell cycle, and development in the model parasite Trypanosoma brucei. African trypanosomes possess hundreds of variant surface glycoprotein (VSG) genes, but only one is expressed from a telomeric expression site (ES) at any given time. We found that the expression of a second VSG alone is sufficient to silence the active VSG gene and directionally attenuate the ES by disruptor of telomeric silencing-1B (DOT1B)-mediated histone methylation. Three conserved expression-site-associated genes (ESAGs) appear to serve as signal for ES attenuation. Their depletion causes G1-phase dormancy and reversible initiation of the slender-to-stumpy differentiation pathway. ES-attenuated slender bloodstream trypanosomes gain full developmental competence for transformation to the tsetse fly stage. This surprising connection between antigenic variation and developmental progression provides an unexpected point of attack against the deadly sleeping sickness. DOI: http://dx.doi.org/10.7554/eLife.02324.001 African sleeping sickness is a potentially lethal disease that is caused by a parasite called T. brucei and spread by tsetse flies. Like many of the parasites that cause tropical diseases, T. brucei employs genetic trickery to evade the immune systems of humans and other mammals. This involves changing the variant surface glycoprotein (VSG) coat that surrounds the parasite on a regular basis in order to remain one step ahead of the immune system of its host: while the immune system looks for invaders wearing a particular coat, the parasites are spreading through the host in a completely different coat. To infect other hosts, the parasite must undergo changes that allow it to re-infect the tsetse fly. Therefore, besides the ‘antigenic variation’ that allows it to change its surface coat when it is in the blood of its host, T. brucei must undergo a more fundamental metamorphosis before it is capable of colonizing the tsetse fly. However, many details of the changes that allow the parasites to re-infect flies are not understood. T. brucei has several hundred VSG genes clustered in about 15 regions known as expression sites, but only a single expression site is active at any given time. Each expression site also contains a number of other genes known as expression site-associated genes (ESAGs). Antigenic variation can occur as a result of different VSG genes within the same expression site being expressed as proteins, or when the active expression site is silenced and another expression site is activated. This is another process that is not fully understood. Batram et al. now reveal that the expression of VSG genes, antigenic variation and the changes that allow the parasites to re-infect flies are all related to each other. This suggests that the expression site could provide a new point of attack in the fight against African sleeping sickness. DOI: http://dx.doi.org/10.7554/eLife.02324.002