Hyrina, Anastasia, Holdorf, Meghan and Jones, Christopher (2019) ZCCHC14 is a novel host factor that is required for Hepatitis B virus RNA polyadenylation. Cell reports, 29 (10). pp. 2970-2978. ISSN 2211-1247

Abstract

The hallmark of chronic hepatitis B virus (CHB) infection is the presence of high levels of circulating non-infectious small lipid vesicles containing HBV surface antigen (HBsAg). Although rare, sustained HBsAg loss is the idealized endpoint of any CHB therapy and is considered a functional cure. A novel, potent and orally bioavailable small molecule RG7834 has been previously reported to inhibit HBsAg expression putatively targeting host non-canonical poly(A) RNA polymerases, PAP-associated domain-containing protein 5 and 7 (PAPD5 and PAPD7). In this study, we describe a forward genetic screen exploiting CRISPR-mediated genome-wide editing to identify novel host factors required for HBsAg expression and to gain further insights into the mechanism of RG7834. Several genes were enriched in a cell population resisting to RG7834-mediating HBsAg inhibition, including PAPD5 and a novel host factor zinc finger CCHC-type containing 14 (ZCCHC14). The role of ZCCHC14, PAPD5 as well as its homolog PAPD7 were further confirmed by the siRNA knockdown studies which phenotypically similarly to RG7834 were associated with the strong reduction in polyA tails of HBV-specific RNAs. In addition, as seen previously with RG7834, inhibition of HBsAg expression by ZCCHC14 and PAPD5/7 complex requires intact SL? in the HBV post-transcriptional regulatory elements. In conclusion, we identify ZCCHC14 as a novel cellular factor, which acts together with the PAPD5 and PAPD7 complex to polyadenylate HBV transcripts and as a new therapeutic target for the HBV cure.

Item Type:	Article
Date Deposited:	04 Jan 2020 18:55
Last Modified:	04 Jan 2020 18:55
URI:	https://oak.novartis.com/id/eprint/38509