Oxysterol-binding protein is a phosphatidylinositol 4-kinase effector required for HCV replication membrane integrity and cholesterol trafficking.
Oxysterol-binding protein is a phosphatidylinositol 4-kinase effector required for HCV replication membrane integrity and cholesterol trafficking.
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DOI：
10.1053/j.gastro.2014.02.002
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发表时间：
2014-05
期刊：
影响因子：
29.4
通讯作者：
Tai AW
中科院分区：
文献类型：
--
作者：
Wang H;Perry JW;Lauring AS;Neddermann P;De Francesco R;Tai AW
正义RNA病毒改造细胞膜，产生专门的膜室进行病毒复制。一些RNA病毒，包括脊髓灰质炎病毒和丙型肝炎病毒（HCV），需要磷脂酰肌醇（PI） 4激酶进行复制。然而，目前尚不清楚PI - 4激酶及其产物PI(4)P如何促进宿主膜重组和病毒复制。此外，尽管被称为膜网的HCV复制区被认为富含胆固醇，但其发生的机制尚未阐明。我们的目的是鉴定和表征HCV复制中的PI - 4激酶效应物。我们采用显微和生化相结合的方法研究了HCV复制、网状形态、细胞内蛋白和PI(4)P的分布以及HCV感染细胞中的胆固醇运输。在表达全长1b基因型复制子或感染HCV JFH-1株的细胞中，采用RNA干扰或小分子抑制PI - 4激酶和氧甾醇结合蛋白（OSBP）的表达。HCV复制和膜网完整性需要OSBP。OSBP以PI - 4激酶依赖的方式被招募到膜网，这两个因素都被发现调节胆固醇向膜网的运输。我们还发现OSBP对脊髓灰质炎病毒感染是必需的，但对登革热病毒则是不必要的。OSBP是HCV感染中的PI - 4激酶效应物，有助于膜网的完整性和胆固醇富集。OSBP也可能是脊髓灰质炎病毒感染中的PI - 4激酶效应物，并可能参与其他需要PI - 4激酶的病毒的复制。
Positive-sense RNA viruses remodel intracellular membranes to generate specialized membrane compartments for viral replication. Several RNA viruses, including poliovirus and hepatitis C virus (HCV), require phosphatidylinositol (PI) 4-kinases for their replication. However, it is not known how PI 4-kinases and their product, PI(4)P, facilitate host membrane reorganization and viral replication. Furthermore, although the HCV replication compartment, known as the membranous web, is believed to be cholesterol-enriched, the mechanisms by which this occurs have not been elucidated. We aimed to identify and characterize a PI 4-kinase effector in HCV replication. We used a combination of microscopic and biochemical methods to study HCV replication, web morphology, the distribution of intracellular protein and PI(4)P, along with cholesterol trafficking in HCV-infected cells. PI 4-kinase and oxysterol-binding protein (OSBP) were inhibited using RNA interference or small molecules in cells expressing a full-length genotype 1b replicon or infected with the JFH-1 strain of HCV. OSBP was required for HCV replication and membranous web integrity. OSBP was recruited to membranous webs in a PI 4-kinase-dependent manner, and both these factors were found to regulate cholesterol trafficking to the web. We also found OSBP to be required for poliovirus infection but dispensable for dengue virus. OSBP is a PI 4-kinase effector in HCV infection, and contributes to the integrity and cholesterol enrichment of the membranous web. OSBP might also be a PI 4-kinase effector in poliovirus infection and could be involved in replication of other viruses that require PI 4-kinases.
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影响因子：
5.4
作者：
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通讯作者：
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DOI：
10.1042/bj20090428
发表时间：
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期刊：
The Biochemical journal
影响因子：
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64.5
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