Architecture and Reactivity of RNA, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, Strasbourg, France.
mBio. 2013 Nov 19;4(6):e00698-13. doi: 10.1128/mBio.00698-13.
Small RNAs play a critical role in host-pathogen interaction. Indeed, small RNA-mediated silencing or RNA interference (RNAi) is one of the earliest forms of antiviral immunity. Although it represents the main defense system against viruses in many organisms, the antiviral role of RNAi has not been clearly proven in higher vertebrates. However, it is well established that their response to viral infection relies on the recognition of viral RNAs by host pattern recognition receptors (PRRs) to trigger activation of the interferon pathway. In the present work, we report the existence of a novel small noncoding RNA population produced in mammalian cells upon RNA virus infection. Using Sindbis virus (SINV) as a prototypic arbovirus model, we profiled the small RNA population of infected cells in both human and African green monkey cell lines. Here, we provide evidence for the presence of discrete small RNAs of viral origin that are not associated with the RNA-induced silencing complex (RISC), that are highly expressed and detected by Northern blot analysis, and that accumulate as 21- to 28-nucleotide (nt) species during infection. We report that the cellular antiviral endoribonuclease RNase L cleaves the viral genome, producing in turn the small RNAs. Surprisingly, we uncovered the presence of a modification on the 3'-end nucleotide of SINV-derived viral small RNAs (SvsRNAs) that might be at the origin of their stability. Altogether, our findings show that stable modified small viral RNAs could represent a novel way to modulate host-virus interaction upon SINV infection.
In a continuous arms race, viruses have to deal with host antiviral responses in order to successfully establish an infection. In mammalian cells, the host defense mechanism relies on the recognition of viral RNAs, resulting in the activation of type I interferons (IFNs). In turn, the expression of many interferon-stimulated genes (ISGs) is induced to inhibit viral replication. Here we report that the cytoplasmic, interferon-induced, cellular endoribonuclease RNase L is involved in the accumulation of a novel small RNA population of viral origin. These small RNAs are produced upon SINV infection of mammalian cells and are stabilized by a 3'-end modification. Altogether, our findings indicate that in our system RNA silencing is not active against Sindbis virus (SINV) and might open the way to a better understanding of the antiviral response mediated by a novel class of small RNAs.
小 RNA 在宿主-病原体相互作用中起着关键作用。事实上，小 RNA 介导的沉默或 RNA 干扰 (RNAi) 是最早形式的抗病毒免疫之一。尽管它代表了许多生物体中对抗病毒的主要防御系统，但 RNAi 的抗病毒作用在高等脊椎动物中尚未得到明确证实。然而，已经确定它们对病毒感染的反应依赖于宿主模式识别受体 (PRR) 对病毒 RNA 的识别，以触发干扰素途径的激活。在本工作中，我们报告了哺乳动物细胞在 RNA 病毒感染后产生的新型小非编码 RNA 群体的存在。我们使用辛德比斯病毒 (SINV) 作为原型虫媒病毒模型，对感染细胞的小 RNA 群体进行了人源和非洲绿猴细胞系的分析。在这里，我们提供了证据表明存在源自病毒的离散小 RNA，它们与 RNA 诱导的沉默复合物 (RISC) 无关，通过 Northern blot 分析高度表达和检测，并在感染过程中积累为 21-28 个核苷酸 (nt) 大小的物质。我们报告说，细胞内抗病毒内切核酸酶 RNase L 切割病毒基因组，从而产生小 RNA。令人惊讶的是，我们发现 SINV 衍生病毒小 RNA (SvsRNAs) 的 3'-末端核苷酸存在修饰，这可能是其稳定性的起源。总之，我们的发现表明，稳定的修饰小病毒 RNA 可能代表了 SINV 感染后调节宿主-病毒相互作用的一种新方法。
在持续的军备竞赛中，病毒必须应对宿主抗病毒反应，才能成功建立感染。在哺乳动物细胞中，宿主防御机制依赖于对病毒 RNA 的识别，导致 I 型干扰素 (IFN) 的激活。反过来，许多干扰素刺激基因 (ISG) 的表达被诱导以抑制病毒复制。在这里，我们报告说，细胞质、干扰素诱导的细胞内切核酸酶 RNase L 参与了源自病毒的新型小 RNA 群体的积累。这些小 RNA 是在哺乳动物细胞感染 SINV 后产生的，并通过 3'-末端修饰稳定。总之，我们的研究结果表明，在我们的系统中，RNA 沉默对辛德比斯病毒 (SINV) 不起作用，这可能为更好地理解由新型小 RNA 介导的抗病毒反应开辟了道路。
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