VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes
VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes
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DOI：
10.1073/pnas.1600344113
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发表时间：
2016-06-28
影响因子：
11.1
通讯作者：
Horn, David
中科院分区：
文献类型：
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作者：
Glover, Lucy;Hutchinson, Sebastian;Horn, David
等位基因排斥支持非洲锥虫的抗原变异和免疫逃避。这些血流寄生虫使用RNA聚合酶-I（pol-I）一次只转录一个端粒变异表面糖蛋白（VSG）基因，产生过量和可转换的VSG外套。我们确定了锥虫VSG排斥-1（VEX 1）使用端粒排他性表达缺陷的遗传筛选。当VEX 1异位表达或耗尽时，VEX 1被活性VSG隔离，其他VSG的沉默失败，分别表示正调控和负调控。正调控影响VSGs和非端粒pol-I转录基因，而负调控主要影响VSGs。负调控VEX 1也影响端粒pol-I-转录的报告构建体，但只有当它们包含块的序列共享同源性与pol-I-转录位点。我们的结论是，由于VEX 1隔离，结合VEX 1依赖的，可能是同源依赖的沉默，限制性的积极调控，驱动一个“赢家通吃”的等位基因排斥机制。
Allelic exclusion underpins antigenic variation and immune evasion in African trypanosomes. These bloodstream parasites use RNA polymerase-I (pol-I) to transcribe just one telomeric variant surface glycoprotein (VSG) gene at a time, producing superabundant and switchable VSG coats. We identified trypanosome VSG exclusion-1 (VEX1) using a genetic screen for defects in telomere-exclusive expression. VEX1 was sequestered by the active VSG and silencing of other VSGs failed when VEX1 was either ectopically expressed or depleted, indicating positive and negative regulation, respectively. Positive regulation affected VSGs and nontelomeric pol-I-transcribed genes, whereas negative regulation primarily affected VSGs. Negative regulation by VEX1 also affected telomeric pol-I-transcribed reporter constructs, but only when they contained blocks of sequence sharing homology with a pol-I-transcribed locus. We conclude that restricted positive regulation due to VEX1 sequestration, combined with VEX1-dependent, possibly homology-dependent silencing, drives a "winner-takes-all" mechanism of allelic exclusion.