Borch Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, IN; Purdue Institute of Inflammation, Immunology, and Infectious Disease (PI4D), Purdue University, West Lafayette, IN.
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN.
J Lipid Res. 2024 Nov;65(11):100663. doi: 10.1016/j.jlr.2024.100663. Epub 2024 Oct 5.
Plasma membrane (PM) domains and order phases have been shown to play a key role in the assembly, release, and entry of several lipid-enveloped viruses. In the present study, we provide a mechanistic understanding of the Ebola virus (EBOV) matrix protein VP40 interaction with PM lipids and their effect on VP40 oligomerization, a crucial step for viral assembly and budding. VP40 matrix formation is sufficient to induce changes in the PM fluidity. We demonstrate that the distance between the lipid headgroups, the fatty acid tail saturation, and the PM order are important factors for the stability of VP40 binding and oligomerization at the PM. The use of FDA-approved drugs to fluidize the PM destabilizes the viral matrix assembly leading to a reduction in budding efficiency. Overall, these findings support an EBOV assembly mechanism that reaches beyond lipid headgroup specificity by using ordered PM lipid regions independent of cholesterol.
质膜（PM）域和有序相已被证明在几种脂质包膜病毒的组装、释放和进入中发挥关键作用。在本研究中，我们深入了解了埃博拉病毒（EBOV）基质蛋白 VP40 与 PM 脂质的相互作用及其对 VP40 寡聚化的影响，VP40 寡聚化为病毒组装和出芽的关键步骤。VP40 基质的形成足以诱导 PM 流动性的变化。我们证明了脂质头部之间的距离、脂肪酸尾部饱和度和 PM 有序性是 VP40 在 PM 上结合和寡聚化稳定性的重要因素。使用 FDA 批准的药物使 PM 流态化会破坏病毒基质的组装，从而降低出芽效率。总的来说，这些发现支持了一种 EBOV 组装机制，该机制超越了脂质头部基团的特异性，利用了不依赖于胆固醇的有序 PM 脂质区域。
