STING-dependent translation inhibition restricts RNA virus replication
STING-dependent translation inhibition restricts RNA virus replication
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DOI：
10.1073/pnas.1716937115
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发表时间：
2018-02-27
影响因子：
11.1
通讯作者：
Kagan, Jonathan C.
中科院分区：
文献类型：
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作者：
Franz, Kate M.;Neidermyer, William J.;Kagan, Jonathan C.
在哺乳动物细胞中，RNA和DNA病毒感染期间发生的IFN应答由不同的信号传导途径激活。RIG-I样受体（RLR）结合病毒RNA并接合接头MAVS（线粒体抗病毒信号传导）以促进IFN表达，而cGAS（cGMP-AMP合酶）结合病毒DNA并通过蛋白STING（IFN基因的刺激物）激活类似途径。在这项研究中，我们证实，STING是不必要的RNA病毒感染过程中诱导IFN的表达，但也发现，STING是需要限制不同的RNA病毒的复制。STING的抗病毒活性与其调节IFN刺激基因的基础表达、激活转录或自噬的能力无关。使用水泡性口炎病毒作为模型，我们确定了STING在感染期间和转染合成RLR配体后抑制翻译的要求。这种抑制发生在翻译起始水平，并限制病毒和宿主蛋白的产生。无法限制翻译使得STING缺陷细胞比野生型对应物更有可能支持生产性病毒感染100倍。遗传分析将RLR的RNA传感与STING依赖的翻译抑制联系起来，独立于MAVS。因此，STING在宿主防御中具有双重功能，调节蛋白质合成以防止RNA病毒感染和调节IFN表达以限制DNA病毒。
In mammalian cells, IFN responses that occur during RNA and DNA virus infections are activated by distinct signaling pathways. The RIG-I-like-receptors (RLRs) bind viral RNA and engage the adaptor MAVS (mitochondrial antiviral signaling) to promote IFN expression, whereas cGAS (cGMP-AMP synthase) binds viral DNA and activates an analogous pathway via the protein STING (stimulator of IFN genes). In this study, we confirm that STING is not necessary to induce IFN expression during RNA virus infection but also find that STING is required to restrict the replication of diverse RNA viruses. The antiviral activities of STING were not linked to its ability to regulate basal expression of IFN-stimulated genes, activate transcription, or autophagy. Using vesicular stomatitis virus as a model, we identified a requirement of STING to inhibit translation during infection and upon transfection of synthetic RLR ligands. This inhibition occurs at the level of translation initiation and restricts the production of viral and host proteins. The inability to restrict translation rendered STING-deficient cells 100 times more likely to support productive viral infections than wild-type counterparts. Genetic analysis linked RNA sensing by RLRs to STING-dependent translation inhibition, independent of MAVS. Thus, STING has dual functions in host defense, regulating protein synthesis to prevent RNA virus infection and regulating IFN expression to restrict DNA viruses.