Cholesterol-Dependent Membrane Deformation by Metastable Viral Capsids Facilitates Entry.
Cholesterol-Dependent Membrane Deformation by Metastable Viral Capsids Facilitates Entry.
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亚稳态病毒衣壳造成的胆固醇依赖性膜变形有利于进入。
DOI：
10.1101/2024.01.10.575085
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Yu,Yan
中科院分区：
文献类型：
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作者：
Jiao,Mengchi;Danthi,Pranav;Yu,Yan
无包膜病毒采用独特的进入机制来破坏和感染宿主细胞。了解这些机制对于制定抗病毒策略至关重要。普遍的观点认为，无包膜病毒释放膜成孔肽来破坏宿主膜。然而，病毒衣壳在该条目中的精确参与仍然难以捉摸。我们的研究提出了直接观察，阐明了亚稳态呼肠孤病毒衣壳在脱壳成部分疏水性中间颗粒时破坏宿主脂质膜的动态独特步骤。使用活细胞和模型膜系统，我们的主要发现是呼肠孤病毒衣壳在胆固醇依赖性过程中主动变形和透化脂质膜。与膜成孔肽不同，这些亚稳态病毒衣壳会引起更广泛的膜扰动，包括出芽、相邻膜之间的桥接和完全破裂。值得注意的是，胆固醇增强了亚病毒颗粒的吸附，导致形成与衣壳大小相当的孔。这种胆固醇依赖性归因于脂质凝结效应，在中等胆固醇水平时尤其突出。此外，我们的结果揭示了膜破坏程度与病毒变体建立感染的效率之间呈正相关。这项研究揭示了衣壳-脂质相互作用在无包膜病毒进入中的关键作用，为胆固醇稳态如何影响病毒感染动态提供了新的见解。
Nonenveloped viruses employ unique entry mechanisms to breach and infect host cells. Understanding these mechanisms is crucial for developing antiviral strategies. Prevailing perspective suggests that nonenveloped viruses release membrane pore-forming peptides to breach host membranes. However, the precise involvement of the viral capsid in this entry remains elusive. Our study presents direct observations elucidating the dynamically distinctive steps through which metastable reovirus capsids disrupt host lipid membranes as they uncoat into partially hydrophobic intermediate particles. Using both live cells and model membrane systems, our key finding is that reovirus capsids actively deform and permeabilize lipid membranes in a cholesterol-dependent process. Unlike membrane pore-forming peptides, these metastable viral capsids induce more extensive membrane perturbations, including budding, bridging between adjacent membranes, and complete rupture. Notably, cholesterol enhances subviral particle adsorption, resulting in the formation of pores equivalent to the capsid size. This cholesterol dependence is attributed to the lipid condensing effect, particularly prominent at an intermediate cholesterol level. Furthermore, our results reveal a positive correlation between membrane disruption extent and efficiency of viral variants in establishing infection. This study unveils the crucial role of capsid-lipid interaction in nonenveloped virus entry, providing new insights into how cholesterol homeostasis influences virus infection dynamics.