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
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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. 作者: StephenW 时间: 2018-11-15 11:50