Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20

Daniela Stadler; Martin Kächele; Alisha N. Jones; Julia Hess; Christian Urban; Jessica Schneider; Yuchen Xia; Andreas Oswald; Firat Nebioglu; Romina Bester; Felix Lasitschka; Marc Ringelhan; Chunkyu Ko; Wen Min Chou; Arie Geerlof; Maarten A. van de Klundert; Jochen M. Wettengel; Peter Schirmacher; Mathias Heikenwälder; Sabrina Schreiner; Ralf Bartenschlager; Andreas Pichlmair; Michael Sattler; Kristian Unger; Ulrike Protzer

doi:10.15252/embr.201949568

Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20

Daniela Stadler, Martin Kächele, Alisha N. Jones, Julia Hess, Christian Urban, Jessica Schneider, Yuchen Xia, Andreas Oswald, Firat Nebioglu, Romina Bester, Felix Lasitschka, Marc Ringelhan, Chunkyu Ko, Wen Min Chou, Arie Geerlof, Maarten A. van de Klundert, Jochen M. Wettengel, Peter Schirmacher, Mathias Heikenwälder, Sabrina SchreinerRalf Bartenschlager, Andreas Pichlmair, Michael Sattler, Kristian Unger, Ulrike Protzer

Chemistry

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	e49568
Journal	EMBO Reports
Volume	22
Issue number	6
DOIs	https://doi.org/10.15252/embr.201949568
State	Published - Jun 4 2021

Keywords

APOBEC3A
HBV
chronic hepatitis B
interferon alpha
interferon gamma

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Genetics

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10.15252/embr.201949568

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Stadler, D., Kächele, M., Jones, A. N., Hess, J., Urban, C., Schneider, J., Xia, Y., Oswald, A., Nebioglu, F., Bester, R., Lasitschka, F., Ringelhan, M., Ko, C., Chou, W. M., Geerlof, A., van de Klundert, M. A., Wettengel, J. M., Schirmacher, P., Heikenwälder, M., ... Protzer, U. (2021). Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20. EMBO Reports, 22(6), Article e49568. https://doi.org/10.15252/embr.201949568

Stadler, D, Kächele, M, Jones, AN, Hess, J, Urban, C, Schneider, J, Xia, Y, Oswald, A, Nebioglu, F, Bester, R, Lasitschka, F, Ringelhan, M, Ko, C, Chou, WM, Geerlof, A, van de Klundert, MA, Wettengel, JM, Schirmacher, P, Heikenwälder, M, Schreiner, S, Bartenschlager, R, Pichlmair, A, Sattler, M, Unger, K & Protzer, U 2021, 'Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20', EMBO Reports, vol. 22, no. 6, e49568. https://doi.org/10.15252/embr.201949568

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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 = "Publisher Copyright: {\textcopyright} 2021 Helmholtz Zentrum Muenchen. Published under the terms of the CC BY NC ND 4.0 license",

year = "2021",

month = jun,

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doi = "10.15252/embr.201949568",

language = "English (US)",

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T1 - Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20

AU - Stadler, Daniela

AU - Kächele, Martin

AU - Jones, Alisha N.

AU - Hess, Julia

AU - Urban, Christian

AU - Schneider, Jessica

AU - Xia, Yuchen

AU - Oswald, Andreas

AU - Nebioglu, Firat

AU - Bester, Romina

AU - Lasitschka, Felix

AU - Ringelhan, Marc

AU - Ko, Chunkyu

AU - Chou, Wen Min

AU - Geerlof, Arie

AU - van de Klundert, Maarten A.

AU - Wettengel, Jochen M.

AU - Schirmacher, Peter

AU - Heikenwälder, Mathias

AU - Schreiner, Sabrina

AU - Bartenschlager, Ralf

AU - Pichlmair, Andreas

AU - Sattler, Michael

AU - Unger, Kristian

AU - Protzer, Ulrike

PY - 2021/6/4

Y1 - 2021/6/4

N2 - 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.

AB - 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.

KW - APOBEC3A

KW - HBV

KW - chronic hepatitis B

KW - interferon alpha

KW - interferon gamma

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DO - 10.15252/embr.201949568

M3 - Article

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AN - SCOPUS:85105379341

SN - 1469-221X

VL - 22

JO - EMBO Reports

JF - EMBO Reports

IS - 6

M1 - e49568

ER -

Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20

Abstract

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