Roby Justin A, Setoh Yin Xiang, Hall Roy A, Khromykh Alexander A
1Australian Infectious Diseases Research Centre, The University of Queensland, Australia 2School of Chemistry and Molecular Biosciences, The University of Queensland, Australia.
J Gen Virol. 2015 Jul;96(Pt 7):1551-69. doi: 10.1099/vir.0.000097. Epub 2015 Feb 23.
Flaviviruses are a group of single-stranded, positive-sense RNA viruses that generally circulate between arthropod vectors and susceptible vertebrate hosts, producing significant human and veterinary disease burdens. Intensive research efforts have broadened our scientific understanding of the replication cycles of these viruses and have revealed several elegant and tightly co-ordinated post-translational modifications that regulate the activity of viral proteins. The three structural proteins in particular - capsid (C), pre-membrane (prM) and envelope (E) - are subjected to strict regulatory modifications as they progress from translation through virus particle assembly and egress. The timing of proteolytic cleavage events at the C-prM junction directly influences the degree of genomic RNA packaging into nascent virions. Proteolytic maturation of prM by host furin during Golgi transit facilitates rearrangement of the E proteins at the virion surface, exposing the fusion loop and thus increasing particle infectivity. Specific interactions between the prM and E proteins are also important for particle assembly, as prM acts as a chaperone, facilitating correct conformational folding of E. It is only once prM/E heterodimers form that these proteins can be secreted efficiently. The addition of branched glycans to the prM and E proteins during virion transit also plays a key role in modulating the rate of secretion, pH sensitivity and infectivity of flavivirus particles. The insights gained from research into post-translational regulation of structural proteins are beginning to be applied in the rational design of improved flavivirus vaccine candidates and make attractive targets for the development of novel therapeutics.
黄病毒是一类单链、正义RNA病毒，通常在节肢动物媒介和易感脊椎动物宿主之间传播，给人类和兽医领域带来了重大疾病负担。大量的研究工作拓宽了我们对这些病毒复制周期的科学认识，并揭示了几种精细且紧密协调的翻译后修饰，这些修饰调节着病毒蛋白的活性。特别是三种结构蛋白——衣壳（C）、前体膜（prM）和包膜（E）——在从翻译到病毒颗粒组装和释放的过程中会经历严格的调控修饰。在C-prM连接处的蛋白水解切割事件的时机直接影响基因组RNA包装到新生病毒颗粒中的程度。在高尔基体转运过程中，宿主弗林蛋白酶对prM进行蛋白水解成熟，促进E蛋白在病毒颗粒表面的重排，暴露出融合环，从而增加颗粒的感染性。prM和E蛋白之间的特定相互作用对颗粒组装也很重要，因为prM充当伴侣蛋白，促进E蛋白正确的构象折叠。只有当prM/E异二聚体形成时，这些蛋白才能有效地分泌。在病毒颗粒转运过程中，向prM和E蛋白添加分支聚糖在调节黄病毒颗粒的分泌速率、pH敏感性和感染性方面也起着关键作用。从对结构蛋白翻译后调控的研究中获得的见解开始应用于改进黄病毒候选疫苗的合理设计，并成为开发新型治疗方法的有吸引力的靶点。
