An engineered mutant of a host phospholipid synthesis gene inhibits viral replication without compromising host fitness
An engineered mutant of a host phospholipid synthesis gene inhibits viral replication without compromising host fitness
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DOI：
10.1074/jbc.ra118.007051
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发表时间：
2019-09-20
影响因子：
4.8
通讯作者：
Wang, Xiaofeng
中科院分区：
文献类型：
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作者：
He, Guijuan;Zhang, Zhenlu;Wang, Xiaofeng
病毒感染普遍依赖于许多被劫持的宿主因素才能成功。因此，有可能通过操纵对病毒复制至关重要的宿主因子来控制病毒感染。鉴于宿主基因可能在某些细胞过程中发挥重要作用，任何成功的病毒控制操作都应不会对宿主适应性产生影响或产生轻微影响。我们以前表明，一组正链RNA病毒丰富的磷脂酰胆碱（PC）在病毒复制的网站。具体而言，雀麦花叶病毒（BMV）复制蛋白1a与PC合成酶（磷脂酰乙醇胺甲基转移酶，Cho 2p）相互作用并将其募集到组装在核周内质网（ER）膜上的病毒复制位点。CHO2基因的缺失抑制BMV复制5倍，然而，它也减缓了宿主细胞的生长。在这里，我们表明，工程Cho2p突变体支持一般PC合成和正常细胞生长，但阻止BMV复制。该突变体与BMV 1a相互作用并共定位，但阻止BMV 1a定位于核周ER膜。错误定位的BMV 1a不能诱导病毒复制复合物的形成。我们的研究证明了一种有效的抗病毒策略，其中宿主脂质合成基因被工程化以控制病毒复制而不影响宿主生长。
Viral infections universally rely on numerous hijacked host factors to be successful. It is therefore possible to control viral infections by manipulating host factors that are critical for viral replication. Given that host genes may play essential roles in certain cellular processes, any successful manipulations for virus control should cause no or mild effects on host fitness. We previously showed that a group of positive-strand RNA viruses enrich phosphatidylcholine (PC) at the sites of viral replication. Specifically, brome mosaic virus (BMV) replication protein 1a interacts with and recruits a PC synthesis enzyme, phosphatidylethanolamine methyltransferase, Cho2p, to the viral replication sites that are assembled on the perinuclear endoplasmic reticulum (ER) membrane. Deletion of the CHO2 gene inhibited BMV replication by 5-fold; however, it slowed down host cell growth as well. Here, we show that an engineered Cho2p mutant supports general PC synthesis and normal cell growth but blocks BMV replication. This mutant interacts and colocalizes with BMV 1a but prevents BMV 1a from localizing to the perinuclear ER membrane. The mislocalized BMV 1a fails to induce the formation of viral replication complexes. Our study demonstrates an effective antiviral strategy in which a host lipid synthesis gene is engineered to control viral replication without comprising host growth.