马球状激酶1是乙型肝炎病毒复制的前病毒宿主因子

StephenW

Polo-like-kinase 1 is a proviral host-factor for hepatitis B virus replication
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    Accepted manuscript online: 26 April 2017Full publication history
    DOI: 10.1002/hep.29236  View/save citation
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ABSTRACT

Chronic Hepatitis B Virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) and current treatments for CHB and HCC are perfectible. Herein, we identified cellular Serine/Threonine Polo-like-kinase 1 (PLK1) as a positive effector of HBV replication. The aim of this study was to demonstrate the proviral role of PLK1 in HBV biosynthesis and validate PLK1 inhibition a potential antiviral strategy.

To this end, we employed physiologically relevant HBV infection models of Primary Human Hepatocytes (PHH) and differentiated HepaRG cells, in conjunction with pharmacologic PLK1 inhibitors, siRNA-mediated knockdown, and overexpression of constitutively active PLK1 (PLK1CA). In addition, humanized liver FRG mouse model was used to determine antiviral effect of PLK1 inhibitor BI-2536 on HBV infection in vivo. Lastly, in vitro PLK1 kinase assays and site-directed mutagenesis were employed to demonstrate HBV core protein (HBc) is a PLK1 substrate.

We demonstrate HBV infection activated cellular PLK1 in PHH and dHepaRG cells. PLK1 inhibition by BI-2536 or siRNA-mediated knockdown suppressed, whereas overexpression of PLK1CA increased HBV DNA biosynthesis, supporting PLK1 effects on viral biosynthesis are specific, and PLK1 is a proviral cellular factor. Significantly, BI-2536 administration to HBV-infected humanized liver FRG mice strongly inhibited HBV infection, validating PLK1 as a novel antiviral target in vivo. The proviral action of PLK1 is associated with the biogenesis of the nucleocapsid, as BI-2536 leads to its decreased intracellular formation/accumulation. In this respect, our studies identified HBc as a PLK1 substrate in vitro, and mapped PLK1 phosphorylation sites on this protein.

PLK1 is a proviral host factor that could be envisaged as a target for combined antiviral and anti-tumoral strategies against HBV infection and HBV mediated carcinogenesis. This article is protected by copyright. All rights reserved.

StephenW

马球状激酶1是乙型肝炎病毒复制的前病毒宿主因子
作者

    在线接受手稿：2017年4月26日全文出版历史
    DOI：10.1002 / hep.29236查看/保存引用
    引用（CrossRef）：0篇文章检查更新

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抽象

慢性乙型肝炎病毒（HBV）感染是肝细胞癌（HCC）的主要危险因素，目前治疗CHB和HCC是完全可行的。在这里，我们确定细胞丝氨酸/苏氨酸马球激酶1（PLK1）作为HBV复制的阳性效应物。本研究的目的是证明PLK1在HBV生物合成中的前病毒作用，并验证了PLK1抑制作用的潜在抗病毒策略。

为此，我们采用与原代人肝细胞（PHH）和分化的HepaRG细胞的生理相关HBV感染模型，结合药理学PLK1抑制剂，siRNA介导的敲低和组成型活性PLK1（PLK1CA）的过表达。此外，人源化肝脏FRG小鼠模型用于测定PLK1抑制剂BI-2536对体内HBV感染的抗病毒作用。最后，体外PLK1激酶测定和定点诱变用于证实HBV核心蛋白（HBc）是一种PLK1底物。

我们在PHH和dHepaRG细胞中显示HBV感染激活的细胞PLK1。抑制BI-2536或siRNA介导的敲低的PLK1抑制，而PLK1CA的过表达增加了HBV DNA生物合成，支持PLK1对病毒生物合成的作用是特异性的，而PLK1是前病毒细胞因子。显着地，对HBV感染的人源化肝脏FRG小鼠的BI-2536施用强烈地抑制HBV感染，验证PLK1作为体内新型抗病毒靶标。 PLK1的前病毒作用与核衣壳的生物发生相关，因为BI-2536导致其细胞内形成/积累减少。在这方面，我们的研究将HBc在体外鉴定为PLK1底物，并在该蛋白上映射PLK1磷酸化位点。

PLK1是一种前病毒宿主因子，可以被设想为组合的抗病毒和抗肿瘤策略针对HBV感染和HBV介导的致癌作用的靶标。本文受版权保护。版权所有。