Identification of the Intragenomic Promoter Controlling Hepatitis E Virus Subgenomic RNA Transcription.
Identification of the Intragenomic Promoter Controlling Hepatitis E Virus Subgenomic RNA Transcription.
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DOI：
10.1128/mbio.00769-18
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发表时间：
2018-05-08
期刊：
影响因子：
6.4
通讯作者：
Ploss A
中科院分区：
文献类型：
--
作者：
Ding Q;Nimgaonkar I;Archer NF;Bram Y;Heller B;Schwartz RE;Ploss A
在发展中国家和工业化国家，每年约有2000万例戊型肝炎病毒（HEV）感染。大多数感染是自限性的，但它们可导致免疫功能低下患者的慢性感染和肝硬化，以及孕妇的死亡。由于缺乏足够的实验平台，HEV复制的机制仍不完全清楚。HEV进行不对称基因组复制，但它产生额外的亚基因组（SG）RNA编码病毒衣壳和病毒孔蛋白在部分重叠的开放阅读框。使用一种新的反式互补系统，我们映射的intragenomic亚基因组启动子调节SG RNA的合成。该顺式作用元件在所有八种HEV基因型中高度保守，并且当该元件突变时，它废除颗粒组装和释放。我们的工作定义了以前不受重视的病毒调控元件，并提供了这种新兴的人类病原体的细胞内基因组动态的第一个深入的看法。戊型肝炎病毒是一种引起严重肝病的新兴病原体。HEV的遗传信息编码在RNA中。基因组RNA最初被复制成互补的反基因组RNA，该反基因组RNA是合成更多基因组RNA和所谓的亚基因组RNA的模板。在这项研究中，我们确定了精确的区域内的戊型肝炎病毒基因组中的亚基因组RNA的合成开始。该区域内的核苷酸在HEV的遗传上不同的变体中是保守的，突出了该片段对病毒的普遍重要性。为了确定这种调节元件，我们开发了一种新的实验系统，该系统是一种功能强大的工具，具有广泛的实用性，可以机械地解剖许多其他鲜为人知的HEV功能元件。
Approximately 20 million hepatitis E virus (HEV) infections occur annually in both developing and industrialized countries. Most infections are self-limiting, but they can lead to chronic infections and cirrhosis in immunocompromised patients, and death in pregnant women. The mechanisms of HEV replication remain incompletely understood due to scarcity of adequate experimental platforms. HEV undergoes asymmetric genome replication, but it produces an additional subgenomic (SG) RNA encoding the viral capsid and a viroporin in partially overlapping open reading frames. Using a novel transcomplementation system, we mapped the intragenomic subgenomic promoter regulating SG RNA synthesis. This cis-acting element is highly conserved across all eight HEV genotypes, and when the element is mutated, it abrogates particle assembly and release. Our work defines previously unappreciated viral regulatory elements and provides the first in-depth view of the intracellular genome dynamics of this emerging human pathogen. HEV is an emerging pathogen causing severe liver disease. The genetic information of HEV is encoded in RNA. The genomic RNA is initially copied into a complementary, antigenomic RNA that is a template for synthesis of more genomic RNA and for so-called subgenomic RNA. In this study, we identified the precise region within the HEV genome at which the synthesis of the subgenomic RNA is initiated. The nucleotides within this region are conserved across genetically distinct variants of HEV, highlighting the general importance of this segment for the virus. To identify this regulatory element, we developed a new experimental system that is a powerful tool with broad utility to mechanistically dissect many other poorly understood functional elements of HEV.