全基因组CRISPR筛选确定ZCCHC14是产生乙型肝炎表面抗原所需的

StephenW

Cell Rep. 2019 Dec 3;29(10):2970-2978.e6. doi: 10.1016/j.celrep.2019.10.113.
A Genome-wide CRISPR Screen Identifies ZCCHC14 as a Host Factor Required for Hepatitis B Surface Antigen Production.
Hyrina A1, Jones C2, Chen D2, Clarkson S3, Cochran N3, Feucht P2, Hoffman G3, Lindeman A3, Russ C3, Sigoillot F3, Tsang T2, Uehara K2, Xie L2, Ganem D2, Holdorf M2.
Author information

1
    Novartis Institutes for BioMedical Research, Emeryville, CA 94608, USA. Electronic address: [email protected].
2
    Novartis Institutes for BioMedical Research, Emeryville, CA 94608, USA.
3
    Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.

Abstract

A hallmark of chronic hepatitis B (CHB) virus infection is the presence of high circulating levels of non-infectious small lipid HBV surface antigen (HBsAg) vesicles. Although rare, sustained HBsAg loss is the idealized endpoint of any CHB therapy. A small molecule, RG7834, has been previously reported to inhibit HBsAg expression by targeting terminal nucleotidyltransferase proteins 4A and 4B (TENT4A and TENT4B). In this study, we describe a genome-wide CRISPR screen to identify other potential host factors required for HBsAg expression and to gain further insights into the mechanism of RG7834. We report more than 60 genes involved in regulating HBsAg and identify additional factors involved in RG7834 activity, including a zinc finger CCHC-type containing 14 (ZCCHC14) protein. We show that ZCCHC14, together with TENT4A/B, stabilizes HBsAg expression through HBV RNA tailing, providing a potential new therapeutic target to achieve functional cure in CHB patients.

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
KEYWORDS:

CRISPR; HBV; HBsAg; RG7834; RNA tailing; TENT4B; ZCCHC14; genome-wide screen

PMID:
    31801065
DOI:
    10.1016/j.celrep.2019.10.113

StephenW

Cell Rep.2019年12月3日; 29（10）：2970-2978.e6。 doi：10.1016 / j.celrep.2019.10.113。
全基因组CRISPR筛选确定ZCCHC14是产生乙型肝炎表面抗原所需的宿主因子。
Hyrina A1，Jones C2，Chen D2，Clarkson S3，Cochran N3，Feucht P2，Hoffman G3，Lindeman A3，Russ C3，Sigoillot F3，Tsang T2，Uehara K2，Xie L2，Ganem D2，Holdorf M2。
作者信息

1个
    诺华生物医学研究所，美国，加利福尼亚州94608，埃默里维尔。电子地址：[email protected]。
2
    诺华生物医学研究所，美国，加利福尼亚州94608，埃默里维尔。
3
    诺华生物医学研究所，剑桥，MA 02139，美国。

抽象

慢性乙型肝炎（CHB）病毒感染的标志是存在高循环水平的非感染性小脂质HBV表面抗原（HBsAg）囊泡。尽管很少见，但持续的HBsAg丢失是任何CHB治疗的理想终点。先前已报道过一种小分子RG7834通过靶向末端核苷酸转移酶蛋白4A和4B（TENT4A和TENT4B）抑制HBsAg表达。在这项研究中，我们描述了全基因组CRISPR筛选，以鉴定HBsAg表达所需的其他潜在宿主因子，并进一步了解RG7834的机制。我们报告了涉及调节HBsAg的60多个基因，并确定了涉及RG7834活性的其他因素，包括含14个（ZCCHC14）蛋白的锌指CCHC型。我们显示ZCCHC14与TENT4A / B一起通过HBV RNA拖尾稳定HBsAg表达，提供了潜在的新治疗靶点，可在CHB患者中实现功能性治愈。

版权所有©2019作者。由Elsevier Inc.出版。保留所有权利。
关键字：

CRISPR;乙肝病毒乙肝表面抗原RG7834; RNA拖尾； TENT4B; ZCCHC14；全基因组筛选

PMID：
    31801065
DOI：
    10.1016 / j.celrep.2019.10.113