Membrane interactions and uncoating of Aichi virus, a picornavirus that lacks a VP4
Membrane interactions and uncoating of Aichi virus, a picornavirus that lacks a VP4
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爱知病毒（一种缺乏 VP4 的小核糖核酸病毒）的膜相互作用和脱壳
DOI：
10.1101/2022.01.10.475380
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Kelly J
中科院分区：
文献类型：
--
作者：
Kelly J
科布病毒属是小核糖核酸病毒家族中一个不常见且特征不明显的属，可引起人类、牲畜和宠物的胃肠道疾病。人类kobuvirus爱知病毒（AiV）可导致5岁以下儿童严重胃肠炎和死亡;然而，这是非常罕见的情况。在大多数小核糖核酸病毒（例如，脊髓灰质炎病毒、鼻病毒和口蹄疫病毒），衣壳前体蛋白VP 0被切割成VP 4和VP 2。然而，kobuvirus保留未切割的VP 0。从对其他小核糖核酸病毒的研究中，已知VP 4执行膜中孔形成的基本功能，其促进病毒基因组穿过内体膜转移到细胞质中以进行复制。在这里，我们采用基因组暴露和膜相互作用试验，以证明pH值在AiV脱壳和膜相互作用中起着关键作用。我们证明，在低pH值下孵育改变了衣壳内疏水残基的暴露，增强了基因组暴露，并增强了模型膜的透化。此外，使用肽，我们证明，N端的VP 0介导的膜孔形成模型膜，这表明这起着类似的功能，以VP 4。重要的是，启动感染，病毒必须进入宿主细胞，并提供其基因组到适当的位置。小无包膜RNA病毒家族包括重要的人类和动物病原体，也是了解细胞进入过程的模型。大多数小核糖核酸病毒衣壳含有由VP 0前体裂解产生的内部蛋白VP 4。在进入期间，VP 4从衣壳释放。在肠道病毒中，这形成了一个膜孔，有助于基因组释放到细胞质中。由于高水平的序列相似性，预计它对其他小核糖核酸病毒起相同的作用。一些小核糖核酸病毒，如爱知病毒，保留了完整的VP 0，目前还不清楚这些病毒如何重新排列其衣壳，并诱导膜通透性在VP 4的情况下。在这里，我们使用爱知病毒作为模型VP 0病毒来测试VP 0和VP 4之间的功能保守性。这可以增强对孔功能的理解，并导致开发阻断进入的新型治疗剂。
Kobuviruses are an unusual and poorly characterized genus within the picornavirus family and can cause gastrointestinal enteric disease in humans, livestock, and pets. The human kobuvirus Aichi virus (AiV) can cause severe gastroenteritis and deaths in children below the age of 5 years; however, this is a very rare occurrence. During the assembly of most picornaviruses (e.g., poliovirus, rhinovirus, and foot-and-mouth disease virus), the capsid precursor protein VP0 is cleaved into VP4 and VP2. However, kobuviruses retain an uncleaved VP0. From studies with other picornaviruses, it is known that VP4 performs the essential function of pore formation in membranes, which facilitates transfer of the viral genome across the endosomal membrane and into the cytoplasm for replication. Here, we employ genome exposure and membrane interaction assays to demonstrate that pH plays a critical role in AiV uncoating and membrane interactions. We demonstrate that incubation at low pH alters the exposure of hydrophobic residues within the capsid, enhances genome exposure, and enhances permeabilization of model membranes. Furthermore, using peptides we demonstrate that the N terminus of VP0 mediates membrane pore formation in model membranes, indicating that this plays an analogous function to VP4.IMPORTANCETo initiate infection, viruses must enter a host cell and deliver their genome into the appropriate location. The picornavirus family of small nonenveloped RNA viruses includes significant human and animal pathogens and is also a model to understand the process of cell entry. Most picornavirus capsids contain the internal protein VP4, generated from cleavage of a VP0 precursor. During entry, VP4 is released from the capsid. In enteroviruses this forms a membrane pore, which facilitates genome release into the cytoplasm. Due to high levels of sequence similarity, it is expected to play the same role for other picornaviruses. Some picornaviruses, such as Aichi virus, retain an intact VP0, and it is unknown how these viruses rearrange their capsids and induce membrane permeability in the absence of VP4. Here, we have used Aichi virus as a model VP0 virus to test for conservation of function between VP0 and VP4. This could enhance understanding of pore function and lead to development of novel therapeutic agents that block entry.