The Enterovirus 71 A-particle Forms a Gateway to Allow Genome Release: A CryoEM Study of Picornavirus Uncoating

Since its discovery in 1969, enterovirus 71 (EV71) has emerged as a serious worldwide health threat. This human pathogen of the picornavirus family causes hand, foot, and mouth disease, and also has the capacity to invade the central nervous system to cause severe disease and death. Upon binding to a host receptor on the cell surface, the virus begins a two-step uncoating process, first forming an expanded, altered “A-particle”, which is primed for genome release. In a second step after endocytosis, an unknown trigger leads to RNA expulsion, generating an intact, empty capsid. Cryo-electron microscopy reconstructions of these two capsid states provide insight into the mechanics of genome release. The EV71 A-particle capsid interacts with the genome near the icosahedral two-fold axis of symmetry, which opens to the external environment via a channel ∼10 Å in diameter that is lined with patches of negatively charged residues. After the EV71 genome has been released, the two-fold channel shrinks, though the overall capsid dimensions are conserved. These structural characteristics identify the two-fold channel as the site where a gateway forms and regulates the process of genome release.自1969年被发现以来，肠道病毒71型（enterovirus 71, EV71）已成为全球范围内的重大公共健康威胁。该病毒隶属于小核糖核酸病毒科（Picornaviridae），可引发手足口病，同时具备侵袭中枢神经系统、导致重症疾病乃至死亡的能力。当病毒结合细胞表面的宿主受体后，会启动两步脱衣壳过程：首先形成膨大且构象改变的A颗粒，该颗粒已准备就绪以释放基因组。在内吞作用后的第二阶段，未知的触发因素会促使RNA被排出，进而形成完整的空衣壳。针对这两种衣壳状态的冷冻电子显微镜（cryo-electron microscopy）重构结果，为解析基因组释放的分子机制提供了重要见解。EV71的A颗粒衣壳在二十面体对称二重轴附近与基因组相互作用，该轴通过一条直径约10埃（Å）的通道与外部环境相通，通道表面分布着带负电荷的残基斑块。在EV71基因组释放完成后，该二重通道会发生收缩，但衣壳的整体尺寸得以保持不变。这些结构特征表明，二重通道是形成病毒释放门户并调控基因组释放过程的关键位点。