DDX60L is an interferon-stimulated gene product restricting hepatitis C virus replication in cell culture

O Grunvogel, K Esser-Nobis, Anna Reustle, P Shult, B Muller, Philippe Metz, Martin Trippler, Marc Windisch, Michael FRESE, Marco Binder, Oliver Fackler, Ralf Bartenschlager, Alessia Ruggieri, Volker Lohmann

Research output: Contribution to journalArticle

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Abstract

All major types of interferon (IFN) efficiently inhibit hepatitis C virus (HCV) replication in vitro and in vivo. Remarkably, HCV replication is not sensitive to IFN-¿ in the hepatoma cell line Huh6, despite an intact signaling pathway. We performed transcriptome analyses between Huh6 and Huh-7 cells to identify effector genes of the IFN-¿ response and thereby identified the DExD/H box helicase DEAD box polypeptide 60-like (DDX60L) as a restriction factor of HCV replication. DDX60L and its homolog DEAD box polypeptide 60 (DDX60) were both induced upon viral infection and IFN treatment in primary human hepatocytes. However, exclusively DDX60L knockdown increased HCV replication in Huh-7 cells and rescued HCV replication from type II IFN as well as type I and III IFN treatment, suggesting that DDX60L is an important effector protein of the innate immune response against HCV. In contrast, we found no impact of DDX60L on replication of hepatitis A virus. DDX60L protein was detectable only upon strong ectopic overexpression, displayed a broad cytoplasmic distribution, but caused cytopathic effects under these conditions. DDX60L knockdown did not alter interferon-stimulated gene (ISG) induction after IFN treatment but inhibited HCV replication upon ectopic expression, suggesting that it is a direct effector of the innate immune response. It most likely inhibits viral RNA replication, since we found neither impact of DDX60L on translation or stability of HCV subgenomic replicons nor additional impact on assembly of infectious virus. Similar to DDX60, DDX60L had a moderate impact on RIG-I dependent activation of innate immunity, suggesting additional functions in the sensing of viral RNA.
Original languageEnglish
Pages (from-to)10548-10568
Number of pages21
JournalJournal of Virology
Volume89
Issue number20
DOIs
Publication statusPublished - Oct 2015
Externally publishedYes

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Hepatitis C virus
interferons
Virus Replication
virus replication
Hepacivirus
Interferons
polypeptides
cell culture
Cell Culture Techniques
Peptides
Genes
genes
Innate Immunity
Viral RNA
Hepatitis A virus
Virus Assembly
replicon
Interferon Type I
Replicon
cytopathogenicity

Cite this

Grunvogel, O., Esser-Nobis, K., Reustle, A., Shult, P., Muller, B., Metz, P., ... Lohmann, V. (2015). DDX60L is an interferon-stimulated gene product restricting hepatitis C virus replication in cell culture. Journal of Virology, 89(20), 10548-10568. https://doi.org/10.1128/JVI.01297-15
Grunvogel, O ; Esser-Nobis, K ; Reustle, Anna ; Shult, P ; Muller, B ; Metz, Philippe ; Trippler, Martin ; Windisch, Marc ; FRESE, Michael ; Binder, Marco ; Fackler, Oliver ; Bartenschlager, Ralf ; Ruggieri, Alessia ; Lohmann, Volker. / DDX60L is an interferon-stimulated gene product restricting hepatitis C virus replication in cell culture. In: Journal of Virology. 2015 ; Vol. 89, No. 20. pp. 10548-10568.
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Grunvogel, O, Esser-Nobis, K, Reustle, A, Shult, P, Muller, B, Metz, P, Trippler, M, Windisch, M, FRESE, M, Binder, M, Fackler, O, Bartenschlager, R, Ruggieri, A & Lohmann, V 2015, 'DDX60L is an interferon-stimulated gene product restricting hepatitis C virus replication in cell culture', Journal of Virology, vol. 89, no. 20, pp. 10548-10568. https://doi.org/10.1128/JVI.01297-15

DDX60L is an interferon-stimulated gene product restricting hepatitis C virus replication in cell culture. / Grunvogel, O; Esser-Nobis, K; Reustle, Anna; Shult, P; Muller, B; Metz, Philippe; Trippler, Martin; Windisch, Marc; FRESE, Michael; Binder, Marco; Fackler, Oliver; Bartenschlager, Ralf; Ruggieri, Alessia; Lohmann, Volker.

In: Journal of Virology, Vol. 89, No. 20, 10.2015, p. 10548-10568.

Research output: Contribution to journalArticle

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T1 - DDX60L is an interferon-stimulated gene product restricting hepatitis C virus replication in cell culture

AU - Grunvogel, O

AU - Esser-Nobis, K

AU - Reustle, Anna

AU - Shult, P

AU - Muller, B

AU - Metz, Philippe

AU - Trippler, Martin

AU - Windisch, Marc

AU - FRESE, Michael

AU - Binder, Marco

AU - Fackler, Oliver

AU - Bartenschlager, Ralf

AU - Ruggieri, Alessia

AU - Lohmann, Volker

N1 - Copyright © 2015, American Society for Microbiology. All Rights Reserved.

PY - 2015/10

Y1 - 2015/10

N2 - All major types of interferon (IFN) efficiently inhibit hepatitis C virus (HCV) replication in vitro and in vivo. Remarkably, HCV replication is not sensitive to IFN-¿ in the hepatoma cell line Huh6, despite an intact signaling pathway. We performed transcriptome analyses between Huh6 and Huh-7 cells to identify effector genes of the IFN-¿ response and thereby identified the DExD/H box helicase DEAD box polypeptide 60-like (DDX60L) as a restriction factor of HCV replication. DDX60L and its homolog DEAD box polypeptide 60 (DDX60) were both induced upon viral infection and IFN treatment in primary human hepatocytes. However, exclusively DDX60L knockdown increased HCV replication in Huh-7 cells and rescued HCV replication from type II IFN as well as type I and III IFN treatment, suggesting that DDX60L is an important effector protein of the innate immune response against HCV. In contrast, we found no impact of DDX60L on replication of hepatitis A virus. DDX60L protein was detectable only upon strong ectopic overexpression, displayed a broad cytoplasmic distribution, but caused cytopathic effects under these conditions. DDX60L knockdown did not alter interferon-stimulated gene (ISG) induction after IFN treatment but inhibited HCV replication upon ectopic expression, suggesting that it is a direct effector of the innate immune response. It most likely inhibits viral RNA replication, since we found neither impact of DDX60L on translation or stability of HCV subgenomic replicons nor additional impact on assembly of infectious virus. Similar to DDX60, DDX60L had a moderate impact on RIG-I dependent activation of innate immunity, suggesting additional functions in the sensing of viral RNA.

AB - All major types of interferon (IFN) efficiently inhibit hepatitis C virus (HCV) replication in vitro and in vivo. Remarkably, HCV replication is not sensitive to IFN-¿ in the hepatoma cell line Huh6, despite an intact signaling pathway. We performed transcriptome analyses between Huh6 and Huh-7 cells to identify effector genes of the IFN-¿ response and thereby identified the DExD/H box helicase DEAD box polypeptide 60-like (DDX60L) as a restriction factor of HCV replication. DDX60L and its homolog DEAD box polypeptide 60 (DDX60) were both induced upon viral infection and IFN treatment in primary human hepatocytes. However, exclusively DDX60L knockdown increased HCV replication in Huh-7 cells and rescued HCV replication from type II IFN as well as type I and III IFN treatment, suggesting that DDX60L is an important effector protein of the innate immune response against HCV. In contrast, we found no impact of DDX60L on replication of hepatitis A virus. DDX60L protein was detectable only upon strong ectopic overexpression, displayed a broad cytoplasmic distribution, but caused cytopathic effects under these conditions. DDX60L knockdown did not alter interferon-stimulated gene (ISG) induction after IFN treatment but inhibited HCV replication upon ectopic expression, suggesting that it is a direct effector of the innate immune response. It most likely inhibits viral RNA replication, since we found neither impact of DDX60L on translation or stability of HCV subgenomic replicons nor additional impact on assembly of infectious virus. Similar to DDX60, DDX60L had a moderate impact on RIG-I dependent activation of innate immunity, suggesting additional functions in the sensing of viral RNA.

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KW - Cell Survival

KW - DEAD Box Protein 58

KW - DEAD-box RNA Helicases/antagonists & inhibitors

KW - Gene Expression Regulation

KW - Genes, Reporter

KW - Genotype

KW - Hepacivirus/drug effects

KW - Hepatitis A virus/drug effects

KW - Hepatocytes/drug effects

KW - Host-Pathogen Interactions

KW - Humans

KW - Immunity, Innate

KW - Interferon-gamma/pharmacology

KW - Luciferases/genetics

KW - Primary Cell Culture

KW - Protein Isoforms/antagonists & inhibitors

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KW - Replicon

KW - Signal Transduction

KW - Transcriptome

KW - Virus Replication/genetics

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