Glycosphingolipid GM3 is Indispensable for Dengue Virus Genome Replication.
Glycosphingolipid GM3 is Indispensable for Dengue Virus Genome Replication.
复制标题
鞘糖脂 GM3 对于登革热病毒基因组复制是不可或缺的。
DOI：
10.7150/ijbs.15641
复制
发表时间：
2016
影响因子：
9.2
通讯作者：
Dai J
中科院分区：
文献类型：
--
作者：
Wang K;Wang J;Sun T;Bian G;Pan W;Feng T;Wang P;Li Y;Dai J
登革病毒（DENV）是世界范围内人类最流行的节肢动物传播的病毒性疾病。鞘糖脂（GSL）通过调节病毒与宿主相互作用的各个步骤参与病毒感染。然而，GSL在DENV感染期间的独特作用仍不清楚。在这项研究中，我们使用小鼠黑色素瘤B16细胞及其GSL缺陷突变体对应物GM95细胞来研究GSL对DENV感染的影响。令人惊讶的是，与B16细胞相比，GM95细胞对DENV感染具有高度抗性。用GM3合成酶抑制剂（B16细胞中最丰富的GSL）预处理B16细胞或沉默GM3合成酶T3GAL5显著抑制DENV感染。与B16细胞相比，GM 95细胞对DENV的粘附和内吞作用没有受到影响，但DENV基因组的复制在GM 95细胞中明显受到抑制。此外，GM3与DENV病毒复制复合物共定位于B16细胞内的内质网（ER）上。最后，GM3合成酶抑制剂通过削弱病毒在小鼠脑中的复制而显著降低DENV攻击的乳鼠的死亡率。总之，这些数据表明GM3不是DENV附着和内吞作用所需的，但是对于病毒基因组复制是必需的。以GM3为靶点可能成为抑制DENV感染的新策略。
Dengue virus (DENV) causes the most prevalent arthropod-borne viral disease of humans worldwide. Glycosphingolipids (GSLs) are involved in virus infection by regulating various steps of viral-host interaction. However, the distinct role of GSLs during DENV infection remains unclear. In this study, we used mouse melanoma B16 cells and their GSL-deficient mutant counterpart GM95 cells to study the influence of GSLs on DENV infection. Surprisingly, GM95 cells were highly resistant to DENV infection compared with B16 cells. Pretreatment of B16 cells with synthetase inhibitor of GM3, the most abundant GSLs in B16 cells, or silencing GM3 synthetase T3GAL5, significantly inhibited DENV infection. DENV attachment and endocytosis were not impaired in GM95 cells, but DENV genome replication was obviously inhibited in GM95 cells compared to B16 cells. Furthermore, GM3 was colocalized with DENV viral replication complex on endoplasmic reticulum (ER) inside the B16 cells. Finally, GM3 synthetase inhibitor significantly reduced the mortality rate of suckling mice that challenged with DENV by impairing the viral replication in mouse brain. Taken together, these data indicated that GM3 was not required for DENV attachment and endocytosis, however, essential for viral genome replication. Targeting GM3 could be a novel strategy to inhibit DENV infection.