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Interferon‐induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20
Author(s) -
Stadler Daniela,
Kächele Martin,
Jones Alisha N,
Hess Julia,
Urban Christian,
Schneider Jessica,
Xia Yuchen,
Oswald Andreas,
Nebioglu Firat,
Bester Romina,
Lasitschka Felix,
Ringelhan Marc,
Ko Chunkyu,
Chou WenMin,
Geerlof Arie,
Klundert Maarten A,
Wettengel Jochen M,
Schirmacher Peter,
Heikenwälder Mathias,
Schreiner Sabrina,
Bartenschlager Ralf,
Pichlmair Andreas,
Sattler Michael,
Unger Kristian,
Protzer Ulrike
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201949568
Subject(s) - library science , art history , art , computer science
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.