@article{7620b36fd3af4910a4dc6af8b80f4914,
title = "Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20",
abstract = "Hepatitis B virus (HBV) persists by depositing a covalently closed circular DNA (cccDNA) in the nucleus of infected cells that cannot be targeted by available antivirals. Interferons can diminish HBV cccDNA via APOBEC3-mediated deamination. Here, we show that overexpression of APOBEC3A alone is not sufficient to reduce HBV cccDNA that requires additional treatment of cells with interferon indicating involvement of an interferon-stimulated gene (ISG) in cccDNA degradation. Transcriptome analyses identify ISG20 as the only type I and II interferon-induced, nuclear protein with annotated nuclease activity. ISG20 localizes to nucleoli of interferon-stimulated hepatocytes and is enriched on deoxyuridine-containing single-stranded DNA that mimics transcriptionally active, APOBEC3A-deaminated HBV DNA. ISG20 expression is detected in human livers in acute, self-limiting but not in chronic hepatitis B. ISG20 depletion mitigates the interferon-induced loss of cccDNA, and co-expression with APOBEC3A is sufficient to diminish cccDNA. In conclusion, non-cytolytic HBV cccDNA decline requires the concerted action of a deaminase and a nuclease. Our findings highlight that ISGs may cooperate in their antiviral activity that may be explored for therapeutic targeting.",
keywords = "APOBEC3A, HBV, chronic hepatitis B, interferon alpha, interferon gamma",
author = "Daniela Stadler and Martin K{\"a}chele and Jones, {Alisha N.} and Julia Hess and Christian Urban and Jessica Schneider and Yuchen Xia and Andreas Oswald and Firat Nebioglu and Romina Bester and Felix Lasitschka and Marc Ringelhan and Chunkyu Ko and Chou, {Wen Min} and Arie Geerlof and {van de Klundert}, {Maarten A.} and Wettengel, {Jochen M.} and Peter Schirmacher and Mathias Heikenw{\"a}lder and Sabrina Schreiner and Ralf Bartenschlager and Andreas Pichlmair and Michael Sattler and Kristian Unger and Ulrike Protzer",
note = "Funding Information: We thank Nehal Omar, Aaron Selmeier, and Veronika Gei{\ss}ler for excellent technical support and Lotte Gl{\"u}ck for coordination of liver tissue stainings. We thank Julie Lucifora (INSERM, Lyon, France) for generating HepaRG‐TR‐NTCP cells and Florian Vondran (Medical School Hannover, Germany) for providing primary human hepatocytes. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Projektnummer 272983813—TRR 179 (to UP, RBa, AP, SS, and MH) and TRR 237 (to AP) and by a research grant of ALIOS BioPharma to Technical University of Munich. Open access funding enabled and organized by Projekt DEAL. Funding Information: We thank Nehal Omar, Aaron Selmeier, and Veronika Gei?ler for excellent technical support and Lotte Gl?ck for coordination of liver tissue stainings. We thank Julie Lucifora (INSERM, Lyon, France) for generating HepaRG-TR-NTCP cells and Florian Vondran (Medical School Hannover, Germany) for providing primary human hepatocytes. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)?Projektnummer 272983813?TRR 179 (to UP, RBa, AP, SS, and MH) and TRR 237 (to AP) and by a research grant of ALIOS BioPharma to Technical University of Munich. Open access funding enabled and organized by Projekt DEAL. Publisher Copyright: {\textcopyright} 2021 Helmholtz Zentrum Muenchen. Published under the terms of the CC BY NC ND 4.0 license",
year = "2021",
month = jun,
day = "4",
doi = "10.15252/embr.201949568",
language = "English (US)",
volume = "22",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "6",
}