A New Subclass of Exoribonuclease-Resistant RNA Found in Multiple Genera of Flaviviridae.
A New Subclass of Exoribonuclease-Resistant RNA Found in Multiple Genera of Flaviviridae.
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DOI：
10.1128/mbio.02352-20
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发表时间：
2020-09-29
期刊：
影响因子：
6.4
通讯作者：
Kieft JS
中科院分区：
文献类型：
--
作者：
Szucs MJ;Nichols PJ;Jones RA;Vicens Q;Kieft JS
黄病毒科的成员包括最大的正义单链RNA （+ssRNA）家族之一，分为黄病毒属、鼠疫病毒属、佩吉病毒属和肝病毒属。黄病毒属含有许多与医学相关的病毒，如寨卡病毒、登革热病毒和波瓦桑病毒。在这种情况下，病毒RNA的一部分扭曲成一种独特的三维形状，称为抗外核糖核酸酶RNA (xrRNA)，它阻止细胞“咀嚼”病毒RNA的能力。因此，病毒的部分RNA保持完整，这部分受保护的部分对病毒感染很重要。已知这些xrrna出现在黄病毒中，但它们是否存在于该家族的其他成员中尚不清楚。在这项研究中，我们发现了一个新的xrRNA亚类，不仅在黄病毒中发现，而且在其余三个属中也发现。事实上，这些结构化的病毒rna存在于黄病毒科，这表明它们是多种病原体感染策略的重要组成部分，这可能会导致新的研究途径。病毒已经开发出创新的策略来利用细胞机制并克服宿主的抗病毒防御，通常使用特定结构的RNA元件。在黄病毒属（黄病毒科）中发现的例子是，在黄病毒感染期间，致病性亚基因组黄病毒rna （sfRNAs）在细胞中积累。这些sfRNAs是在宿主细胞5 ‘至3 ’外核糖核酸酶降解病毒基因组RNA时形成的，但被位于病毒基因组3 '未翻译区（UTR）的外核糖核酸酶抗性RNA结构（xrRNA）阻断。虽然已知存在于黄病毒科的几个属中，但该家族xrrna的完整分布和多样性尚不清楚。利用最近获得的来自发散型塔玛纳蝙蝠病毒（TABV）的xrRNA的高分辨率结构作为参考，我们使用生物信息学搜索来鉴定黄病毒科其余三个属（Pegivirus、Pestivirus和Hepacivirus）的xrRNA。我们对几个例子进行了生化和结构表征，确定它们是具有保守折叠的真正xrrna。这些新的xrnas表面上看起来与先前描述的xrnas相似，但具有结构差异，使它们与以前的xrnas不同。总的来说，我们已经在黄病毒科的所有四个属中确定了xrRNA的存在，但并非在所有物种中都存在。因此，我们的发现需要调整以前的xrRNA分类方案，并扩大以前已知的xrRNA在黄病毒科的分布。
The members of the Flaviviridae comprise one of the largest families of positive-sense single-stranded RNA (+ssRNA) and are divided into the Flavivirus, Pestivirus, Pegivirus, and Hepacivirus genera. The genus Flavivirus contains many medically relevant viruses such as Zika virus, dengue virus, and Powassan virus. In these, a part of the RNA of the virus twists up into a distinct three-dimensional shape called an exoribonuclease-resistant RNA (xrRNA) that blocks the ability of the cell to “chew up” the viral RNA. Hence, part of the RNA of the virus remains intact, and this protected part is important for viral infection. These xrRNAs were known to occur in flaviviruses, but whether they existed in the other members of the family was not known. In this study, we identified a new subclass of xrRNA found not only in flaviviruses but also in the remaining three genera. The fact that these structured viral RNAs exist throughout the Flaviviridae family suggests they are important parts of the infection strategy of diverse pathogens, which could lead to new avenues of research. Viruses have developed innovative strategies to exploit the cellular machinery and overcome the antiviral defenses of the host, often using specifically structured RNA elements. Examples are found in the Flavivirus genus (in the family Flaviviridae), where during flaviviral infection, pathogenic subgenomic flaviviral RNAs (sfRNAs) accumulate in the cell. These sfRNAs are formed when a host cell 5′ to 3′ exoribonuclease degrades the viral genomic RNA but is blocked by an exoribonuclease-resistant RNA structure (xrRNA) located in the viral genome’s 3′ untranslated region (UTR). Although known to exist in several Flaviviridae genera, the full distribution and diversity of xrRNAs in this family were unknown. Using the recently solved high-resolution structure of an xrRNA from the divergent flavivirus Tamana bat virus (TABV) as a reference, we used bioinformatic searches to identify xrRNAs in the remaining three genera of Flaviviridae: Pegivirus, Pestivirus, and Hepacivirus. We biochemically and structurally characterized several examples, determining that they are genuine xrRNAs with a conserved fold. These new xrRNAs look superficially similar to the previously described xrRNAs but possess structural differences making them distinct from previous classes of xrRNAs. Overall, we have identified the presence of xrRNA in all four genera of Flaviviridae, but not in all species. Our findings thus require adjustments of previous xrRNA classification schemes and expand the previously known distribution of xrRNA in Flaviviridae.