SIRT1和乙型肝炎病毒X蛋白在病毒转录激活中的相互作用

StephenW

Biochim Biophys Acta. 2017 Feb 24. pii: S1874-9399(16)30263-2. doi: 10.1016/j.bbagrm.2017.02.007. [Epub ahead of print]
Interplay between SIRT1 and hepatitis B virus X protein in the activation of viral transcription.Deng JJ1, Kong KE2, Gao WW2, Tang HV2, Chaudhary V2, Cheng Y2, Zhou J3, Chan CP2, Wong DK4, Yuen MF4, Jin DY5.
Author information

• 1School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; Shaanxi Key Laboratory of Biodegradable Materials, College of Chemical Engineering, Northwest University, 229 Taibai Road North, Xi'an 710069, China; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong.
• 2School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong.
• 3Department of Microbiology, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong.
• 4State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong; Department of Medicine, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong.
• 5School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong. Electronic address: [email protected].
  

AbstractHepatitis B virus (HBV) genome is organized into a minichromosome known as covalently closed circular DNA (cccDNA), which serves as the template for all viral transcripts. SIRT1 is an NAD+-dependent protein deacetylase which activates HBV transcription by promoting the activity of cellular transcription factors and coactivators. How SIRT1 and viral transactivator X protein (HBx) might affect each other remains to be clarified. In this study we show synergy and mutual dependence between SIRT1 and HBx in the activation of HBV transcription. All human sirtuins SIRT1 through SIRT7 activated HBV gene expression. The steady-state levels of SIRT1 protein were elevated in HBV-infected liver tissues and HBV-replicating hepatoma cells. SIRT1 interacted with HBx and potentiated HBx transcriptional activity on precore promoter and covalently closed circular DNA (cccDNA) likely through a deacetylase-independent mechanism, leading to more robust production of cccDNA, pregenomic RNA and surface antigen. SIRT1 and HBx proteins were more abundant when both were expressed. SIRT1 promoted the recruitment of HBx as well as cellular transcriptional factors and coactivators such as PGC-1α and FXRα to cccDNA. Depletion of SIRT1 suppressed HBx recruitment. On the other hand, SIRT1 recruitment to cccDNA was compromised when HBx was deficient. Whereas pharmaceutical agonists of SIRT1 such as resveratrol activated HBV transcription, small-molecule inhibitors of SIRT1 including sirtinol and Ex527 exhibited anti-HBV activity. Taken together, our findings revealed not only the interplay between SIRT1 and HBx in the activation of HBV transcription but also new strategies and compounds for developing antivirals against HBV.

Copyright © 2017. Published by Elsevier B.V.

KEYWORDS: HBx; SIRT1; cccDNA; hepatitis B virus; sirtuin

StephenW

Biochim Biophys Acta。 2017 Feb 24.pii：S1874-9399（16）30263-2。 doi：10.1016 / j.bbagrm.2017.02.007。 [打印前的电子版]
SIRT1和乙型肝炎病毒X蛋白在病毒转录激活中的相互作用。
DENJJ1，Kong KE2，Gao WW2，Tang HV2，Chaudhary V2，Cheng Y2，Zhou J3，Chan CP2，Wong DK4，Yuen MF4，Jin DY5。
作者信息

    1香港大学生物医学科学院，香港薄扶林萨松路21号;陕西西北大学化学工程学院生物降解材料重点实验室，西安，白云西路229号，西安710069;香港大学香港薄扶林Sassoon路5号肝脏研究国家重点实验室。
    2香港大学生物医学科学院，香港薄扶林沙宣道21号;香港大学香港薄扶林Sassoon路5号肝脏研究国家重点实验室。
    香港薄扶林薄扶林道102号香港大学微生物学系。
    4香港大学肝脏研究国家重点实验室，香港薄扶林Sassoon路5号;香港薄扶林薄扶林道102号香港大学医学系。
    5香港大学生物医学科学学士，香港薄扶林萨松路21号;香港大学香港薄扶林Sassoon路5号肝脏研究国家重点实验室。电子地址：[email protected]。

抽象

乙型肝炎病毒（HBV）基因组被组织成称为共价闭合环状DNA（cccDNA）的微染色体，其用作所有病毒转录物的模板。 SIRT1是NAD +依赖性蛋白质脱乙酰酶，其通过促进细胞转录因子和共激活因子的活性来激活HBV转录。 SIRT1和病毒反式激活蛋白X蛋白（HBx）如何可能相互影响仍有待澄清。在这项研究中，我们显示SIRT1和HBx在HBV转录激活之间的协同作用和相互依赖。所有人类sirtuins SIRT1通过SIRT7激活HBV基因表达。 SIRT1蛋白的稳态水平在HBV感染的肝组织和HBV复制的肝癌细胞中升高。 SIRT1与HBx相互作用，并且可能通过不依赖脱乙酰酶的机制与前核启动子和共价闭合环状DNA（cccDNA）上的增强的HBx转录活性，导致更强的cccDNA，前基因组RNA和表面抗原的产生。当两者都表达时，SIRT1和HBx蛋白质更丰富。 SIRT1促进HBx以及细胞转录因子和共激活因子如PGC-1α和FXRα到cccDNA的募集。 SIRT1的消耗抑制HBx募集。另一方面，当HBx缺陷时，SIRT1向cccDNA的募集受损。而SIRT1的药物激动剂如白藜芦醇活化的HBV转录，SIRT1的小分子抑制剂包括sirtinol和Ex527显示出抗HBV活性。综合起来，我们的研究结果不仅揭示了SIRT1和HBx之间在HBV转录激活中的相互作用，而且还发现了用于开发抗HBV的抗病毒剂的新策略和化合物。

版权所有©2017.由Elsevier B.V.出版
关键词：

HBx; SIRT1; cccDNA;乙型肝炎病毒; sirtuin

灵魂不屈

感谢分享！

MP4

白藜芦醇还在临床试验，这么看有点悬了