Cellular cholesterol abundance regulates potassium accumulation within endosomes and is an important determinant in bunyavirus entry
Cellular cholesterol abundance regulates potassium accumulation within endosomes and is an important determinant in bunyavirus entry
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DOI：
10.1074/jbc.ra119.007618
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发表时间：
2019-05-03
影响因子：
4.8
通讯作者：
Mankouri, Jamel
中科院分区：
文献类型：
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作者：
Charlton, Frank W.;Hover, Samantha;Mankouri, Jamel
布尼亚病毒目（Bunyavirales）包括500多个分离株，它们感染昆虫、动物和植物，通常与人类的严重和致命疾病有关。布尼亚病毒为了繁殖和致病，必须通过内吞网络将其基因组从细胞外转移到胞质溶胶中。我们之前已经表明，模型布尼亚病毒、布尼亚韦拉病毒（BUNV）和哈扎拉病毒（HAZV）利用成熟内体的钾浓度（[K+]）变化，在适当的内体位置释放其基因组。K+被鉴定为激活病毒融合机制的生化信号，促进病毒和细胞膜之间的融合，从而允许基因组释放。在这项研究中，我们进一步定义的生化先决条件BUNV和HAZV进入和K+依赖。使用药物介导的胆固醇提取沿着病毒进入和K+摄取测定，我们报告了三个主要发现：BUNV和HAZV在内体逃逸过程中需要细胞胆固醇;宿主细胞的胆固醇消耗损害了K+在成熟内体中的积累，揭示了对内体K+稳态的新见解;在感染前用K+引发BUNV和HAZV病毒粒子增加了它们的胆固醇需求。总之，我们的研究结果表明，胆固醇丰度影响内体K+水平，因此，布尼亚病毒感染的效率的模型。用现有的降胆固醇药物抑制布尼亚病毒的能力可能为未来致病性布尼亚病毒的抗病毒干预提供新的选择。
The Bunyavirales order of segmented negative-sense RNA viruses includes more than 500 isolates that infect insects, animals, and plants and are often associated with severe and fatal disease in humans. To multiply and cause disease, bunyaviruses must translocate their genomes from outside the cell into the cytosol, achieved by transit through the endocytic network. We have previously shown that the model bunyaviruses Bunyamwera virus (BUNV) and Hazara virus (HAZV) exploit the changing potassium concentration ([K+]) of maturing endosomes to release their genomes at the appropriate endosomal location. K+ was identified as a biochemical cue to activate the viral fusion machinery, promoting fusion between viral and cellular membranes, consequently permitting genome release. In this study, we further define the biochemical prerequisites for BUNV and HAZV entry and their K+ dependence. Using drug-mediated cholesterol extraction along with viral entry and K+ uptake assays, we report three major findings: BUNV and HAZV require cellular cholesterol during endosomal escape; cholesterol depletion from host cells impairs K+ accumulation in maturing endosomes, revealing new insights into endosomal K+ homeostasis; and priming BUNV and HAZV virions with K+ before infection alleviates their cholesterol requirement. Taken together, our findings suggest a model in which cholesterol abundance influences endosomal K+ levels and, consequently, the efficiency of bunyavirus infection. The ability to inhibit bunyaviruses with existing cholesterol-lowering drugs may offer new options for future antiviral interventions for pathogenic bunyaviruses.