title: IFN regulatory factor 1 restricts hepatitis E virus replication by activating STAT1 to induce antiviral IFN-stimulated genes.
abstract: IFN regulatory factor 1 (IRF1) is one of the most important IFN-stimulated genes (ISGs) in cellular antiviral immunity. Although hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide, how ISGs counteract HEV infection is largely unknown. This study was conducted to investigate the effect of IRF1 on HEV replication. Multiple cell lines were used in 2 models that harbor HEV. In different HEV cell culture systems, IRF1 effectively inhibited HEV replication. IRF1 did not trigger IFN production, and chromatin immunoprecipitation sequencing data analysis revealed that IRF1 bound to the promoter region of signal transducers and activators of transcription 1 (STAT1). Functional assay confirmed that IRF1 could drive the transcription of STAT1, resulting in elevation of total and phosphorylated STAT1 proteins and further activating the transcription of a panel of downstream antiviral ISGs. By pharmacological inhibitors and RNAi-mediated gene-silencing approaches, we revealed that antiviral function of IRF1 is dependent on the JAK-STAT cascade. Furthermore, induction of ISGs and the anti-HEV effect of IRF1 overlapped that of IFNα, but was potentiated by ribavirin. We demonstrated that IRF1 effectively inhibits HEV replication through the activation of the JAK-STAT pathway, and the subsequent transcription of antiviral ISGs, but independent of IFN production.-Xu, L., Zhou, X., Wang, W., Wang, Y., Yin, Y., van der Laan, L. J. W., Sprengers, D., Metselaar, H. J., Peppelenbosch, M. P., Pan, Q. IFN regulatory factor 1 restricts hepatitis E virus replication by activating STAT1 to induce antiviral IFN-stimulated genes.
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; and.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; and.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; and.
authors.forename: Wenshi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; and.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; and.
authors.forename: Yuebang
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Surgery, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Luc J W van der
authors.initials: LJ
authors.lastname: Laan
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; and.
authors.forename: Dave
authors.initials: D
authors.lastname: Sprengers
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; and.
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; and.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; and q.pan@erasmusmc.nl.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
mesh_terms: D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D016752:Hepatitis E virus / Q000302:isolation & purification*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014779:Virus Replication / Q000502:physiology
chemical_list: D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor
keywords: innate immunity; ribavirin; transcription