Lipid-specific oligomerization of the Marburg virus matrix protein VP40 is regulated by two distinct interfaces for virion assembly.
Lipid-specific oligomerization of the Marburg virus matrix protein VP40 is regulated by two distinct interfaces for virion assembly.
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DOI：
10.1016/j.jbc.2021.100796
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Stahelin RV
中科院分区：
文献类型：
--
作者：
Amiar S;Husby ML;Wijesinghe KJ;Angel S;Bhattarai N;Gerstman BS;Chapagain PP;Li S;Stahelin RV
马尔堡病毒（MARV）是一种携带负义RNA基因组的脂包膜病毒，在撒哈拉以南非洲地区引起病毒性出血热的零星暴发。MARV从宿主细胞质膜组装和出芽，其中MARV基质蛋白（mVP 40）二聚体与质膜内小叶处的阴离子脂质缔合，并经历动态和广泛的自寡聚化进入结构基质层。MARV基质层赋予病毒粒子丝状形状和稳定性，但宿主脂质如何调节mVP 40寡聚化大多是未知的。使用体外和细胞技术，我们提出了一个mVP 40组装模型，突出了两个不同的寡聚化接口：（N-末端结构域[NTD]和C-末端结构域[CTD]）在mVP 40。NTD和CTD寡聚化界面突变体的细胞研究证明了每个界面在基质组装中的重要性。组装步骤包括蛋白质运输至质膜、诱导蛋白质富集的同源多聚化、质膜流动性变化和质膜处的伸长。采用抗坏血酸过氧化物酶衍生物（APEX）-透射电子显微镜方法密切评估野生型mVP 40和NTD和CTD寡聚化界面突变体的病毒颗粒的超微结构定位和形成。总之，这些研究提出了病毒体组装期间mVP 40在质膜上寡聚化和组装的机制模型，其需要与磷脂酰丝氨酸相互作用以进行NTD-NTD相互作用，并与磷脂酰肌醇-4，5-二磷酸相互作用以进行适当的CTD-CTD相互作用。这些发现在理解脂质包膜病毒从宿主细胞质膜出芽以及靶向蛋白质-蛋白质或脂质-蛋白质相互作用以抑制病毒出芽的潜在策略方面具有更广泛的意义。
Marburg virus (MARV) is a lipid-enveloped virus harboring a negative-sense RNA genome, which has caused sporadic outbreaks of viral hemorrhagic fever in sub-Saharan Africa. MARV assembles and buds from the host cell plasma membrane where MARV matrix protein (mVP40) dimers associate with anionic lipids at the plasma membrane inner leaflet and undergo a dynamic and extensive self-oligomerization into the structural matrix layer. The MARV matrix layer confers the virion filamentous shape and stability but how host lipids modulate mVP40 oligomerization is mostly unknown. Using in vitro and cellular techniques, we present a mVP40 assembly model highlighting two distinct oligomerization interfaces: the (N-terminal domain [NTD] and C-terminal domain [CTD]) in mVP40. Cellular studies of NTD and CTD oligomerization interface mutants demonstrate the importance of each interface in matrix assembly. The assembly steps include protein trafficking to the plasma membrane, homo-multimerization that induced protein enrichment, plasma membrane fluidity changes, and elongations at the plasma membrane. An ascorbate peroxidase derivative (APEX)-transmission electron microscopy method was employed to closely assess the ultrastructural localization and formation of viral particles for wildtype mVP40 and NTD and CTD oligomerization interface mutants. Taken together, these studies present a mechanistic model of mVP40 oligomerization and assembly at the plasma membrane during virion assembly that requires interactions with phosphatidylserine for NTD–NTD interactions and phosphatidylinositol-4,5-bisphosphate for proper CTD–CTD interactions. These findings have broader implications in understanding budding of lipid-enveloped viruses from the host cell plasma membrane and potential strategies to target protein–protein or lipid–protein interactions to inhibit virus budding.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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DOI：
10.1073/pnas.250277297
发表时间：
2000-12-05
影响因子：
11.1
作者：
Harty, RN;Brown, ME;Hayes, FP
通讯作者：
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影响因子：
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