A deletion polymorphism in the Caenorhabditis elegans RIG-I homolog disables viral RNA dicing and antiviral immunity.
A deletion polymorphism in the Caenorhabditis elegans RIG-I homolog disables viral RNA dicing and antiviral immunity.
复制标题
Caenorhabdision秀丽隐杆线虫中的删除多态性RIG-I同源物可以禁用病毒RNA DICING和抗病毒免疫。
DOI：
10.7554/elife.00994
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发表时间：
2013-10-08
期刊：
影响因子：
7.7
通讯作者：
Miska EA
中科院分区：
文献类型：
--
作者：
Ashe A;Bélicard T;Le Pen J;Sarkies P;Frézal L;Lehrbach NJ;Félix MA;Miska EA
RNA干扰在植物和动物细胞中防御病毒感染。秀丽隐杆线虫及其自然病原体--正链RNA病毒奥赛（Orsay virus）是近年来发现的一种新的宿主-病毒相互作用的动物模型。利用C.通过对线虫野生种群和数量性状基因座作图的研究，我们确定了保守的drh-1基因（编码RIG-I样解旋酶）中的159个碱基对缺失是病毒敏感性的主要决定因素。我们发现DRH-1是启动抗病毒RNAi途径和产生病毒衍生的siRNA（viRNA）所必需的。在哺乳动物中，含有RIG-I结构域的蛋白质响应于RNA病毒感染而触发基于干扰素的先天免疫途径。我们在C的工作elegans证明了RIG-I结构域在病毒识别中具有古老的作用。我们提出RIG-I作为模块化的病毒识别因子，将病毒识别与不同的效应途径（包括RNAi和干扰素应答）偶联。http://dx.doi.org/10.7554/eLife.00994.001从细菌到哺乳动物，大多数生物体都至少有一个基本的免疫系统，可以检测和防御病原体，特别是病毒。这种防御机制被称为先天免疫系统，它使用传感器蛋白来识别病毒RNA，然后动员其他免疫成分来攻击入侵者。用于破坏病毒的特定机制在物种之间是不同的。在哺乳动物中，一种名为RIG-1的蛋白质与病毒RNA结合并激活导致干扰素产生的信号通路：干扰素是一种免疫蛋白质，以其“干扰”病毒复制的能力命名。植物和昆虫不使用干扰素，而是使用一种称为RNA干扰的机制，其中长的双链RNA被切割成较短的片段。线虫C.秀丽线虫也利用RNA干扰对抗病毒，但与昆虫和植物相反，蠕虫不具有一组专门参与抗病毒反应的RNA干扰酶。然而，它们确实表达一种称为DRH-1的蛋白质，该蛋白质与哺乳动物中发现的RIG-I蛋白质有关。探讨DRH-1是否参与了C. Ashe等感染了97株秀丽隐杆线虫。他们用一种病毒对来自世界各地的秀丽线虫进行了测试，结果表明，某些菌株对病毒比其他菌株更敏感，某些菌株表现出完全的抵抗力。通过比较敏感株和耐药株，Ashe等人揭示了病毒的敏感性是由编码DRH-1的基因突变引起的。进一步的实验表明，DRH-1是RNA干扰的第一步。Ashe等人因此鉴定了RIG-1在启动抗病毒应答中的保守作用，并提出该蛋白质将病毒识别与不同进化组中的不同防御机制偶联。DOI：http://dx.doi.org/10.7554/eLife.00994.002网站
RNA interference defends against viral infection in plant and animal cells. The nematode Caenorhabditis elegans and its natural pathogen, the positive-strand RNA virus Orsay, have recently emerged as a new animal model of host-virus interaction. Using a genome-wide association study in C. elegans wild populations and quantitative trait locus mapping, we identify a 159 base-pair deletion in the conserved drh-1 gene (encoding a RIG-I-like helicase) as a major determinant of viral sensitivity. We show that DRH-1 is required for the initiation of an antiviral RNAi pathway and the generation of virus-derived siRNAs (viRNAs). In mammals, RIG-I-domain containing proteins trigger an interferon-based innate immunity pathway in response to RNA virus infection. Our work in C. elegans demonstrates that the RIG-I domain has an ancient role in viral recognition. We propose that RIG-I acts as modular viral recognition factor that couples viral recognition to different effector pathways including RNAi and interferon responses. DOI: http://dx.doi.org/10.7554/eLife.00994.001 Most organisms—from bacteria to mammals—have at least a rudimentary immune system that can detect and defend against pathogens, particularly viruses. This defense mechanism, which is known as the innate immune system, uses sensor proteins to recognize viral RNA, and then mobilizes other immune components to attack the invaders. The specific mechanisms used to destroy viruses differ between species. In mammals, a protein called RIG-1 binds to viral RNA and activates a signaling pathway that leads to the production of interferons: immune proteins named after their ability to ‘interfere’ with viral replication. Plants and insects do not use interferons, but instead use a mechanism called RNA interference, in which long double-stranded RNAs are cleaved into shorter fragments. The nematode worm C. elegans also deploys RNA interference against viruses but, in contrast to insects and plants, worms do not possess a specific set of RNA interference enzymes that participate solely in the antiviral response. They do, however, express a protein called DRH-1 that is related to the RIG-I protein found in mammals. To investigate whether DRH-1 contributes to innate immunity in C. elegans, Ashe et al. infected 97 strains of C. elegans from around the world with a virus, and showed that some strains were more sensitive to the virus than others, with certain strains showing complete resistance. By comparing a sensitive strain with a resistant one, Ashe et al. revealed that viral sensitivity was caused by a mutation in the gene encoding DRH-1. Further experiments showed that DRH-1 is required for the first step in RNA interference. Ashe et al. have thus identified a conserved role for RIG-1 in initiating antiviral responses, and propose that the protein couples virus recognition to distinct defense mechanisms in different evolutionary groups. DOI: http://dx.doi.org/10.7554/eLife.00994.002