Monoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex
Monoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex
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DOI：
10.1038/s41467-019-10823-8
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发表时间：
2019-07-09
影响因子：
16.6
通讯作者：
Horn, David
中科院分区：
文献类型：
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作者：
Faria, Joana;Glover, Lucy;Horn, David
真核生物中最大的基因家族都受到等位基因排斥，但单等位基因选择和遗传的机制仍不清楚。在这里，我们描述了一个蛋白复合物维持变异表面糖蛋白（VSG）的等位基因排斥和抗原变异的布氏锥虫寄生虫。VSG排斥1（VEX 1）蛋白结合端粒VSG相关染色质和VEX 2，无义介导的衰变解旋酶，UPF 1的直系同源物。VEX 1和VEX 2以RNA聚合酶-I转录依赖的方式组装，并维持活性的亚端粒VSG相关转录区室。当VEX蛋白耗尽时，VSG转录物和VSG外壳变得高度异质。此外，DNA复制相关的染色质组装因子CAF-1结合并特异性维持DNA复制后的VEX 1区室化。因此，VX复合物控制VSG排斥，而CAF-1维持与活性VSG相关的VX复合物遗传。值得注意的是，哺乳动物中的VEX 2直系同源物和CAF-1也涉及排斥和遗传功能。在锥虫中，这些因子维持了一种高效的典型免疫逃避策略。
The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. Here, we describe a protein complex sustaining variant surface glycoprotein (VSG) allelic exclusion and antigenic variation in Trypanosoma brucei parasites. The VSG-exclusion-1 (VEX1) protein binds both telomeric VSG-associated chromatin and VEX2, an ortholog of nonsense-mediated-decay helicase, UPF1. VEX1 and VEX2 assemble in an RNA polymerase-I transcription-dependent manner and sustain the active, subtelomeric VSG-associated transcription compartment. VSG transcripts and VSG coats become highly heterogeneous when VEX proteins are depleted. Further, the DNA replication-associated chromatin assembly factor, CAF-1, binds to and specifically maintains VEX1 compartmentalisation following DNA replication. Thus, the VEX-complex controls VSG-exclusion, while CAF-1 sustains VEX-complex inheritance in association with the active-VSG. Notably, the VEX2-orthologue and CAF-1 in mammals are also implicated in exclusion and inheritance functions. In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy.