The specific SM molecular species that these endogenous SM species interacted with HCV nonstructural 5B polymerase to enhance viral replication

脂质是病毒生命周期中影响宿主与病原体相互作用的关键成分。在本研究中，我们探讨了丙型肝炎病毒感染对鞘磷脂代谢的影响，特别是对内源性SM水平的影响，以及丙型肝炎病毒复制与内源性SM分子种类的关系。我们证明了丙型肝炎病毒可以诱导编码鞘磷脂(SM)合成酶的基因表达。我们观察到在人类肝细胞和丙型肝炎病毒复制所在的抗洗涤剂膜(DRM)组分中，总的和单个的鞘磷脂分子种类都有相关的增加。SGMS-1的表达与丙型肝炎病毒复制密切相关。用嗜肝性丝氨酸棕榈酰基转移酶抑制剂NA808抑制鞘脂的生物合成，抑制了丙型肝炎病毒-RNA的产生，同时也干扰了鞘脂的代谢。此外，我们鉴定了组成DRM组分的特定SM分子物种，并证明这些内源性SM物种与丙型肝炎病毒非结构5B聚合酶相互作用以促进病毒复制。我们的结果显示，丙型肝炎病毒改变鞘脂代谢以促进病毒复制，为丙型肝炎病毒复制复合体的形成和宿主脂类在丙型肝炎病毒生命周期中的参与提供了新的见解。

Lipids are key components in the viral life cycle that affect host-pathogen interactions. In this study, we investigated the effect of HCV infection on sphingolipid metabolism, especially on endogenous SM levels, and the relationship between HCV replication and endogenous SM molecular species. We demonstrated that HCV induces the expression of the genes encoding sphingomyelin(SM) synthases. We observed associated increases of both total and individual sphingolipid molecular species, as assessed in human hepatocytes and in the detergent-resistant membrane(DRM) fraction in which HCV replicates. SGMS-1 expression had a strong correlation with HCV replication. Inhibition of sphingolipid biosynthesis with a hepatotropic serine palmitoyltransferase inhibitor, NA808, suppressed HCV-RNA production while also interfering with sphingolipid metabolism. Further, we identified the specific SM molecular species that comprise the DRM fraction and demonstrated that these endogenous SM species interacted with HCV nonstructural 5B polymerase to enhance viral replication. Our results reveal that HCV alters sphingolipid metabolism to promote viral replication, providing new insights into the formation of the HCV replication complex and the involvement of host lipids in the HCV life cycle.