Division of Biological Sciences, University of California, San Diego, CA 92093, USA.
Viruses. 2012 Oct 19;4(10):2340-58. doi: 10.3390/v4102340.
Eukaryotes possess seven different phosphoinositides (PIPs) that help form the unique signatures of various intracellular membranes. PIPs serve as docking sites for the recruitment of specific proteins to mediate membrane alterations and integrate various signaling cascades. The spatio-temporal regulation of PI kinases and phosphatases generates distinct intracellular hubs of PIP signaling. Hepatitis C virus (HCV), like other plus-strand RNA viruses, promotes the rearrangement of intracellular membranes to assemble viral replication complexes. HCV stimulates enrichment of phosphatidylinositol 4-phosphate (PI4P) pools near endoplasmic reticulum (ER) sites by activating PI4KIIIα, the kinase responsible for generation of ER-specific PI4P pools. Inhibition of PI4KIIIα abrogates HCV replication. PI4P, the most abundant phosphoinositide, predominantly localizes to the Golgi and plays central roles in Golgi secretory functions by recruiting effector proteins involved in transport vesicle generation. The PI4P effector proteins also include the lipid-transfer and structural proteins such as ceramide transfer protein (CERT), oxysterol binding protein (OSBP) and Golgi phosphoprotein 3 (GOLPH3) that help maintain Golgi-membrane composition and structure. Depletion of Golgi-specific PI4P pools by silencing PI4KIIIβ, expression of dominant negative CERT and OSBP mutants, or silencing GOLPH3 perturb HCV secretion. In this review we highlight the role of PIPs and specifically PI4P in the HCV life cycle.
真核生物拥有七种不同的磷酸肌醇（PIPs），这些 PIPs 有助于形成各种细胞内膜的独特特征。PIPs 作为特定蛋白质的停靠位点，有助于介导膜的改变，并整合各种信号级联反应。PI 激酶和磷酸酶的时空调节产生了不同的 PIP 信号细胞内中心。丙型肝炎病毒（HCV）与其他正链 RNA 病毒一样，促进细胞内膜的重排以组装病毒复制复合物。HCV 通过激活 PI4KIIIα（负责生成 ER 特异性 PI4P 池的激酶），刺激内质网（ER）部位附近的磷脂酰肌醇 4-磷酸（PI4P）池的富集。PI4KIIIα 的抑制作用会阻断 HCV 的复制。PI4P 是最丰富的磷酸肌醇，主要定位于高尔基体，并通过招募参与运输囊泡生成的效应蛋白，在高尔基体分泌功能中发挥核心作用。PI4P 效应蛋白还包括脂质转移和结构蛋白，如神经酰胺转移蛋白（CERT）、氧化固醇结合蛋白（OSBP）和高尔基体磷蛋白 3（GOLPH3），它们有助于维持高尔基体膜的组成和结构。通过沉默 PI4KIIIβ、表达显性负性 CERT 和 OSBP 突变体，或沉默 GOLPH3，耗尽高尔基体特异性 PI4P 池，会扰乱 HCV 的分泌。在这篇综述中，我们强调了 PIPs 特别是 PI4P 在 HCV 生命周期中的作用。
