Insight into the multifunctional RNA synthesis machine of rabies virus.
Insight into the multifunctional RNA synthesis machine of rabies virus.
复制标题
深入了解狂犬病病毒的多功能RNA合成机器。
DOI：
10.1073/pnas.2000120117
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发表时间：
2020
影响因子：
11.1
通讯作者：
Fodor E
中科院分区：
文献类型：
--
作者：
Fodor E
狂犬病病毒（RABV）是人类和动物致命性神经系统疾病的病原体。它是从受感染的动物，主要是家犬，通过咬或抓挠的唾液传播给人类。狂犬病是通过给家犬和家猫接种疫苗来控制的，但RABV每年仍导致5万多人死亡，特别是在家犬接种率较低的发展中国家。在人类中，狂犬病可以通过在暴露前或暴露后立即接种疫苗来预防，但没有直接针对病毒的特异性抗病毒药物（1）。在PNAS中，Horwitz et al. (2)提出了一个高分辨率的电子冷冻显微镜结构的RNA合成机器的RABV，提供了有价值的机制洞察其活动和开辟了道路，朝着发展抗病毒的方法，这种致命的病毒。RABV属于一组负链RNA病毒，包括许多人类病原体，如流感病毒，呼吸道合胞病毒（RSV），埃博拉病毒和麻疹病毒。这些病毒的基因组由一个或多个单链负义RNA分子组成，这些分子总是与病毒核蛋白（N）的多个拷贝组装成兆道尔顿大小的复合物（3）。为了启动感染，病毒如RABV必须首先将其负义RNA转录成mRNA，因此必须在其感染颗粒内携带RNA依赖性RNA聚合酶。这些病毒聚合酶是多功能机器，不仅将负链RNA转录成mRNA，而且还通过互补的复制中间体反基因组复制基因组。除了催化RNA合成外，这些聚合酶还确保病毒转录物受到5′-帽结构的保护。这可以通过夺帽机制实现，包括通过帽结合和核酸内切酶功能从宿主加帽RNA中窃取帽，或者使用加帽和甲基转移酶从头合成5′帽结构，其编码在与聚合酶结构域相同的多肽中（图1）（4）。
Rabies virus (RABV) is the causative agent of a fatal neurological disease in humans and animals. It is transmitted to humans from infected animals, mainly domestic dogs, through their saliva by biting or by scratching. Rabies is controlled by vaccination of domestic dogs and cats, but RABV nevertheless kills more than 50,000 people annually, especially in developing countries where vaccination rates in domestic dogs are lower. In humans, rabies is preventable by vaccination prior to or immediately after exposure, but there are no specific antiviral drugs available that target the virus directly (1). In PNAS, Horwitz et al.(2) present a high-resolution electron cryomicroscopy structure of the RNA synthesis machine of RABV, providing valuable mechanistic insight into its activities and opening up the way toward developing antiviral approaches for this fatal virus.RABV belongs to the group of negative-strand RNA viruses that includes many human pathogens such as the influenza viruses, respiratory syncytial virus (RSV), Ebola virus, and measles virus. The genomes of these viruses consist of one or more single-stranded, negative-sense RNA molecules that are always assembled with multiple copies of viral nucleoprotein (N) into megadalton-sized complexes (3). In order to initiate infection, viruses such as RABV must first transcribe their negative-sense RNA into mRNA and therefore must carry an RNA-dependent RNA polymerase within their infectious particle. These viral polymerases are multifunctional machines that not only transcribe the negative-strand RNA into mRNA but also replicate the genome through a complementary replicative intermediate, the antigenome. In addition to catalyzing RNA synthesis, these polymerases also ensure that viral transcripts are protected with a 5′-cap structure. This is achieved either by a cap-snatching mechanism that involves stealing caps from host capped RNAs through cap-binding and endonuclease functions, or de novo synthesis of a 5′-cap structure using capping and methyltransferase enzymes, which are encoded in the same polypeptide as the polymerase domains (Fig. 1)(4).