小柯机器人

2021年8月18日，《自然》杂志在线发表了美国科学家的一项最新研究成果。加州大学旧金山分校Raul Andino、斯坦福大学Judith Frydman等研究人员合作发现，协同翻译的脯氨酰羟化对黄病毒的生物生成至关重要。

研究人员将多聚核糖体的蛋白质组分析与功能基因组学和药理学干预结合起来，从而确定肠道病毒和黄病毒是如何重塑宿主多聚核糖体来合成病毒蛋白并使宿主蛋白生产失效的。研究人员发现，感染脊髓灰质炎、登革热或寨卡病毒会明显地改变多聚核糖体的组成，而核心核糖体的化学计量却没有重大变化。这些病毒使用不同的策略将一套共同的翻译启动和RNA监控因子从多聚核糖体中驱逐出去，同时招募病毒生物生成特别需要的宿主机器。瞄准这些专门的病毒多聚核糖体可以为抗病毒干预提供一种新的方法。

例如，研究人员发现寨卡和登革热都使用胶原蛋白脯氨酸羟化机制来介导病毒多聚蛋白中保守的脯氨酸残基的共翻译修饰。对脯氨酸羟化的遗传或药物抑制会损害新生病毒多聚蛋白的折叠，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聚体重塑并降低病毒产量。这些研究结果描述了病毒-宿主交界上多聚核糖体特化的模块化性质，并建立了一个强大的策略来确定选择性抗病毒干预的靶标。

据介绍，病毒性病原体是对全世界公共健康的持续威胁。分析它们对宿主生物合成途径的依赖性可导致有效的抗病毒疗法。

附：英文原文

Title: Cotranslational prolyl hydroxylation is essential for flavivirus biogenesis

Author: Aviner, Ranen, Li, Kathy H., Frydman, Judith, Andino, Raul

Issue&Volume: 2021-08-18

Abstract: Viral pathogens are an ongoing threat to public health worldwide. Analysing their dependence on host biosynthetic pathways could lead to effective antiviral therapies1. 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.

DOI: 10.1038/s41586-021-03851-2

Source: https://www.nature.com/articles/s41586-021-03851-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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