PAPD5 / 7是乙型肝炎病毒RNA稳定化所需的新型宿主因子

StephenW

PAPD5/7 are novel host factors that are required for Hepatitis B virus RNA stabilization
Henrik Mueller
Anaïs Lopez
Philipp Tropberger
Steffen Wildum
Josephine Schmaler
Lykke Pedersen
Xingchun Han
Yongguang Wang
Søren Ottosen
Song Yang
John A.T. Young
Hassan Javanbakht
First published: 26 October 2018
https://doi.org/10.1002/hep.30329

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.30329

ePDFPDF
Tools
Share
Abstract

RG7834 is a potent orally bioavailable small‐molecule inhibitor of Hepatitis B virus (HBV) gene expression, that belongs to the dihydroquinolizinone (DHQ) chemical class and uniquely blocks production of both viral DNA and antigens. In this study, we used DHQ compounds as tools in a compound‐based adaptation version of the yeast three hybrid screen to identify the cognate cellular protein targets, the non‐canonical poly(A) RNA polymerases PAP‐associated domain‐containing protein 5 and 7 (PAPD5 and PAPD7). Interaction with RG7834 was mapped to the catalytic domains of the two cellular enzymes. The role of PAPD5 and PAPD7 in HBV replication was confirmed by oligonucleotide‐mediated knockdown studies which phenocopied the result seen with RG7834‐treated HBV‐infected hepatocytes. The greatest effect on HBV gene expression was seen when PAPD5 and PAPD7 mRNAs were simultaneously knocked down suggesting that the two cellular proteins play a redundant role in maintaining HBV mRNA levels. Also, as seen previously with RG7834 treatment, PAPD5 and PAPD7 knockdown led to destabilization and degradation of HBV mRNA without impacting production of viral RNA transcripts. Conclusions: We identify PAPD5 and PAPD7 as novel cellular host factors required for HBV RNA stabilization and as new therapeutic targets for the HBV cure.

This article is protected by copyright. All rights reserved.

StephenW

PAPD5 / 7是乙型肝炎病毒RNA稳定化所需的新型宿主因子
亨里克穆勒
AnaïsLopez
Philipp Tropberger
Steffen Wildum
约瑟芬·施马勒
Lykke Pedersen
韩兴春
王永光
SørenOttosen
宋阳
约翰A.T.年轻
哈桑贾万巴克特
首次发表：2018年10月26日
https://doi.org/10.1002/hep.30329

本文已被接受发布并经过完整的同行评审，但尚未通过编辑，排版，分页和校对过程，这可能导致此版本与记录版本之间存在差异。请引用本文为doi：10.1002 / hep.30329

ePDFPDF
工具
分享
抽象

RG7834是一种有效的口服生物可利用的小分子乙型肝炎病毒（HBV）基因表达抑制剂，属于二氢喹嗪酮（DHQ）化学类，独特地阻断病毒DNA和抗原的产生。在这项研究中，我们使用DHQ化合物作为酵母三杂交筛选的基于化合物的适应版本中的工具来鉴定同源细胞蛋白质靶标，非经典聚（A）RNA聚合酶PAP相关结构域蛋白质5和7（PAPD5和PAPD7）。与RG7834的相互作用定位于两种细胞酶的催化结构域。 PAPD5和PAPD7在HBV复制中的作用通过寡核苷酸介导的敲低研究证实，该研究表明用RG7834处理的HBV感染的肝细胞观察到的结果。当PAPD5和PAPD7 mRNA同时被敲低时，观察到对HBV基因表达的最大影响，表明两种细胞蛋白在维持HBV mRNA水平中发挥多余作用。此外，如先前用RG7834处理所见，PAPD5和PAPD7敲低导致HBV mRNA的去稳定化和降解，而不影响病毒RNA转录物的产生。结论：我们将PAPD5和PAPD7鉴定为HBV RNA稳定所需的新型细胞宿主因子，并作为HBV治愈的新治疗靶点。

本文受版权保护。版权所有。

newchinabok

感谢分享，关注