A Genome-wide CRISPR Screen Identifies ZCCHC14 as a Host Factor Required for Hepatitis B Surface Antigen ProductionAuthor links open overlay panelAnastasiaHyrina13
ChristopherJones1DarleneChen1ScottClarkson2NadireCochran2PaulFeucht1GregoryHoffman2AliciaLindeman2CarstenRuss2FredericSigoillot2TiffanyTsang1KyokoUehara1LiliXie1DonGanem1MeghanHoldorf1
https://doi.org/10.1016/j.celrep.2019.10.113Get rights and content
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Highlights•Genome-wide CRISPR screen identifies host factors regulating HBsAg expression •ZCCHC14 and TENT4A/B stabilize HBsAg expression through RNA tailing •ZCCHC14 forms a complex with TENT4B and the HBV PRE •RG7834 inhibits the enzymatic activity of TENT4A/B within the ZCCHC14-HBV PRE complex
SummaryA 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.
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发表于 2020-1-22 20:19
