Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
Department of Biology and Genetics, Stanford University, Stanford, CA, USA.
Nature. 2021 Aug;596(7873):558-564. doi: 10.1038/s41586-021-03851-2. Epub 2021 Aug 18.
Viral pathogens are an ongoing threat to public health worldwide. Analysing their dependence on host biosynthetic pathways could lead to effective antiviral therapies. Here we integrate proteomic analyses of polysomes with functional genomics and pharmacological interventions to define how enteroviruses and flaviviruses remodel host polysomes to synthesize viral proteins and disable host protein production. We find that infection with polio, dengue or Zika virus markedly modifies polysome composition, without major changes to core ribosome stoichiometry. These viruses use different strategies to evict a common set of translation initiation and RNA surveillance factors from polysomes while recruiting host machineries that are specifically required for viral biogenesis. Targeting these specialized viral polysomes could provide a new approach for antiviral interventions. For example, we find that both Zika and dengue use the collagen proline hydroxylation machinery to mediate cotranslational modification of conserved proline residues in the viral polyprotein. Genetic or pharmacological inhibition of proline hydroxylation impairs nascent viral polyprotein folding and induces its aggregation and degradation. Notably, such interventions prevent viral polysome remodelling and lower virus production. Our findings delineate the modular nature of polysome specialization at the virus-host interface and establish a powerful strategy to identify targets for selective antiviral interventions.
病毒病原体是全球公共卫生的持续威胁。分析它们对宿主生物合成途径的依赖关系可能会导致有效的抗病毒疗法。在这里，我们将多核糖体的蛋白质组分析与功能基因组学和药理学干预措施相结合，以确定肠道病毒和黄病毒如何重塑宿主多核糖体来合成病毒蛋白并抑制宿主蛋白的产生。我们发现，脊髓灰质炎病毒、登革热病毒或寨卡病毒的感染会显著改变多核糖体的组成，而核心核糖体的比例没有发生重大变化。这些病毒使用不同的策略从多核糖体中逐出一组常见的翻译起始和 RNA 监测因子，同时招募专门用于病毒生物发生的宿主机制。针对这些专门的病毒多核糖体可能为抗病毒干预提供一种新方法。例如，我们发现寨卡病毒和登革热病毒都利用胶原蛋白脯氨酸羟化酶机制来介导病毒多蛋白中保守脯氨酸残基的共翻译修饰。脯氨酸羟化的遗传或药理学抑制会损害新生病毒多蛋白的折叠，并诱导其聚集和降解。值得注意的是，这种干预措施可以防止病毒多核糖体的重塑并降低病毒产量。我们的研究结果描绘了病毒-宿主界面上多核糖体特化的模块化性质，并建立了一种强大的策略来确定选择性抗病毒干预的靶标。
