One striking characteristic of certain herpesviruses is their ability to induce rapid and widespread RNA decay in order to gain access to host resources. This phenotype is induced by viral endoribonucleases, including SOX in Kaposi's sarcoma-associated herpesvirus (KSHV), muSOX in murine gammaherpesvirus 68 (MHV68), BGLF5 in Epstein-Barr virus (EBV), and vhs in herpes simplex virus 1 (HSV-1). Here, we performed comparative transcriptome sequencing (RNA-seq) upon expression of these herpesviral endonucleases in order to characterize their effect on the host transcriptome. Consistent with previous reports, we found that approximately two-thirds of transcripts were downregulated in cells expressing any of these viral endonucleases. Among the transcripts spared from degradation, we uncovered a cluster of transcripts that systematically escaped degradation from all tested endonucleases. Among these escapees, we identified C19ORF66 and reveal that this transcript is protected from degradation by its 3' untranslated region (UTR). We then show that C19ORF66 is a potent KSHV restriction factor by impeding early viral gene expression, suggesting that its ability to escape viral cleavage may be an important component of the host response to viral infection. Collectively, our comparative approach is a powerful tool to pinpoint key regulators of the viral-host interplay and led us to uncover a novel KSHV regulator.IMPORTANCE Viruses are master regulators of the host gene expression machinery. This is crucial to promote viral infection and to dampen host immune responses. Many viruses, including herpesviruses, express RNases that reduce host gene expression through widespread mRNA decay. However, it emerged that some mRNAs escape this fate, although it has been difficult to determine whether these escaping transcripts benefit viral infection or instead participate in an antiviral mechanism. To tackle this question, we compared the effect of the herpesviral RNases on the human transcriptome and identified a cluster of transcripts consistently escaping degradation from all tested endonucleases. Among the protected mRNAs, we identified the transcript C19ORF66 and showed that it restricts Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Collectively, these results provide a framework to explore how the control of RNA fate in the context of viral-induced widespread mRNA degradation may influence the outcome of viral infection.

中文翻译：

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C19ORF66广泛逃避了病毒诱导的核酸内切酶切割，并限制了卡波西氏肉瘤相关疱疹病毒。

某些疱疹病毒的一个显着特征是它们能够诱导迅速而广泛的RNA衰变从而获得宿主资源的能力。这种表型是由病毒内切核糖核酸酶诱导的，包括卡波西氏肉瘤相关疱疹病毒（KSHV）中的SOX，鼠γ疱疹病毒68（MHV68）中的muSOX，爱泼斯坦-巴尔病毒（EBV）中的BGLF5和单纯疱疹病毒1（HSV-1）中的vhs。 ）。在这里，我们对这些疱疹病毒核酸内切酶的表达进行了比较转录组测序（RNA-seq），以表征它们对宿主转录组的作用。与以前的报告一致，我们发现表达这些病毒核酸内切酶中任何一种的细胞中约有三分之二的转录物被下调。在保留下来的成绩单中，我们发现了一系列转录本，可从所有测试的核酸内切酶系统地逃脱降解。在这些逃逸物中，我们鉴定出C19ORF66并揭示了该转录本受其3'非翻译区（UTR）的保护而免于降解。然后，我们通过阻止早期病毒基因表达，表明C19ORF66是有效的KSHV限制因子，表明其逃避病毒切割的能力可能是宿主对病毒感染反应的重要组成部分。总的来说，我们的比较方法是确定病毒-宿主相互作用的关键调控因子的有力工具，并促使我们发现了一种新颖的KSHV调控因子。重要信息病毒是宿主基因表达机制的主要调控因子。这对于促进病毒感染和抑制宿主免疫反应至关重要。许多病毒，包括疱疹病毒，表达通过广泛的mRNA衰变降低宿主基因表达的RNase。然而，尽管很难确定这些逃避的转录本是否有利于病毒感染或参与抗病毒机制，但仍有一些mRNA逃脱了这一命运。为了解决这个问题，我们比较了疱疹病毒核糖核酸酶对人类转录组的影响，并确定了一系列转录本，这些转录本始终避开了所有测试的核酸内切酶的降解。在受保护的mRNA中，我们鉴定了C19ORF66转录本，并显示它限制了卡波西氏肉瘤相关疱疹病毒（KSHV）感染。总的来说，这些结果提供了一个框架，以探索在病毒引起的广泛的mRNA降解情况下对RNA命运的控制如何影响病毒感染的结果。