Goubau Delphine, Schlee Martin, Deddouche Safia, Pruijssers Andrea J, Zillinger Thomas, Goldeck Marion, Schuberth Christine, Van der Veen Annemarthe G, Fujimura Tsutomu, Rehwinkel Jan, Iskarpatyoti Jason A, Barchet Winfried, Ludwig Janos, Dermody Terence S, Hartmann Gunther, Reis e Sousa Caetano
Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
Nature. 2014 Oct 16;514(7522):372-375. doi: 10.1038/nature13590. Epub 2014 Aug 10.
Mammalian cells possess mechanisms to detect and defend themselves from invading viruses. In the cytosol, the RIG-I-like receptors (RLRs), RIG-I (retinoic acid-inducible gene I; encoded by DDX58) and MDA5 (melanoma differentiation-associated gene 5; encoded by IFIH1) sense atypical RNAs associated with virus infection. Detection triggers a signalling cascade via the adaptor MAVS that culminates in the production of type I interferons (IFN-α and β; hereafter IFN), which are key antiviral cytokines. RIG-I and MDA5 are activated by distinct viral RNA structures and much evidence indicates that RIG-I responds to RNAs bearing a triphosphate (ppp) moiety in conjunction with a blunt-ended, base-paired region at the 5'-end (reviewed in refs 1, 2, 3). Here we show that RIG-I also mediates antiviral responses to RNAs bearing 5'-diphosphates (5'pp). Genomes from mammalian reoviruses with 5'pp termini, 5'pp-RNA isolated from yeast L-A virus, and base-paired 5'pp-RNAs made by in vitro transcription or chemical synthesis, all bind to RIG-I and serve as RIG-I agonists. Furthermore, a RIG-I-dependent response to 5'pp-RNA is essential for controlling reovirus infection in cultured cells and in mice. Thus, the minimal determinant for RIG-I recognition is a base-paired RNA with 5'pp. Such RNAs are found in some viruses but not in uninfected cells, indicating that recognition of 5'pp-RNA, like that of 5'ppp-RNA, acts as a powerful means of self/non-self discrimination by the innate immune system.
哺乳动物细胞拥有检测并抵御入侵病毒的机制。在细胞质中，视维甲酸诱导基因I样受体（RLRs），即视维甲酸诱导基因I（RIG-I；由DDX58编码）和黑色素瘤分化相关基因5（MDA5；由IFIH1编码）可识别与病毒感染相关的非典型RNA。这种识别通过接头蛋白线粒体抗病毒信号蛋白（MAVS）触发信号级联反应，最终导致I型干扰素（IFN-α和β；以下简称IFN）的产生，IFN是关键的抗病毒细胞因子。RIG-I和MDA5由不同的病毒RNA结构激活，大量证据表明，RIG-I可识别5'端带有三磷酸（ppp）基团且具有平端碱基配对区域的RNA（参考文献1、2、3中有相关综述）。在此，我们表明RIG-I也介导对带有5'-二磷酸（5'pp）的RNA的抗病毒反应。具有5'pp末端的哺乳动物呼肠孤病毒基因组、从酵母L-A病毒中分离出的5'pp-RNA，以及通过体外转录或化学合成制备的碱基配对5'pp-RNA，均能与RIG-I结合并作为RIG-I激动剂。此外，对5'pp-RNA的RIG-I依赖性反应对于控制培养细胞和小鼠中的呼肠孤病毒感染至关重要。因此，RIG-I识别的最小决定因素是带有5'pp的碱基配对RNA。此类RNA存在于某些病毒中，但不存在于未感染的细胞中，这表明对5'pp-RNA的识别，与对5'ppp-RNA的识别一样，是先天免疫系统进行自我/非自我区分的有力手段。
