Visualization of conformational changes and membrane remodeling leading to genome delivery by viral class-II fusion machinery.
Visualization of conformational changes and membrane remodeling leading to genome delivery by viral class-II fusion machinery.
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DOI：
10.1038/s41467-022-32431-9
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发表时间：
2022-08-15
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
基孔肯雅病毒（CHIKV）是一种人类病原体，通过ii类融合蛋白介导的低ph激活的内吞膜融合将其基因组传递到宿主细胞质。虽然预融合，二十面体CHIKV结构是可用的，但病毒粒子与膜相互作用的结构表征是有限的。在这里，我们使用低温电子断层扫描可视化了CHIKV的完整膜融合途径，确定了与膜重塑事件相关的关键中间糖蛋白构象。利用亚层析图平均分析了低ph暴露病毒粒子、核衣壳和全长e1糖蛋白融合后的结构特征。与i类融合系统相反，CHIKV通过将扩展的e1 -糖蛋白三聚体突出到靶膜中来实现膜附着。融合过程还具有一个大的半融合膜，过渡到一个宽的孔，以便完整的核衣壳递送。我们的分析为ii类病毒融合系统功能提供了全面的超微结构见解，并对蛋白质介导的膜融合的基本过程进行了直接的机制表征。膜融合是包膜病毒进入细胞的必要条件。在这里，作者使用时间分辨低温电子断层扫描和亚断层扫描平均来捕捉CHIKV（一种医学上重要的甲病毒）膜融合过程中中间体的三维组织和种群进化。
Chikungunya virus (CHIKV) is a human pathogen that delivers its genome to the host cell cytoplasm through endocytic low pH-activated membrane fusion mediated by class-II fusion proteins. Though structures of prefusion, icosahedral CHIKV are available, structural characterization of virion interaction with membranes has been limited. Here, we have used cryo-electron tomography to visualize CHIKV’s complete membrane fusion pathway, identifying key intermediary glycoprotein conformations coupled to membrane remodeling events. Using sub-tomogram averaging, we elucidate features of the low pH-exposed virion, nucleocapsid and full-length E1-glycoprotein’s post-fusion structure. Contrary to class-I fusion systems, CHIKV achieves membrane apposition by protrusion of extended E1-glycoprotein homotrimers into the target membrane. The fusion process also features a large hemifusion diaphragm that transitions to a wide pore for intact nucleocapsid delivery. Our analyses provide comprehensive ultrastructural insights into the class-II virus fusion system function and direct mechanistic characterization of the fundamental process of protein-mediated membrane fusion. Membrane fusion is essential for cellular entry of enveloped viruses. Here, authors use time-resolved cryo-electron tomography and subtomogram averaging to capture 3D organization and population evolution of intermediates during membrane fusion of CHIKV, a medically important alphavirus.
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