title: STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-λ but not by interferon-α.
abstract: Interferon-α (IFN-α) and IFN-λ are structurally distinct cytokines that bind to different receptors, but induce expression of similar sets of genes through Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. The difference between IFN-α and IFN-λ signaling remains poorly understood. Here, using the CRISPR/Cas9 system, we examine the role of STAT1 and STAT2 in the inhibition of hepatitis C virus (HCV) replication by IFN-α and IFN-λ. Treatment with IFN-α increases expression of IFN-stimulated genes (ISGs) such as double-stranded RNA-activated protein kinase (PKR) and decreases viral RNA and protein levels in HCV-infected Huh-7.5 human hepatoma cells. These responses are only partially attenuated by knockout of STAT1 but are abolished by knockout of STAT2. In contrast, the inhibition of HCV replication by IFN-λ is abolished by knockout of STAT1 or STAT2. Microarray analysis reveals that IFN-α but not IFN-λ can induce expression of the majority of ISGs in STAT1 knockout cells. These findings suggest that IFN-α can inhibit HCV replication through a STAT2-dependent but STAT1-independent pathway, whereas IFN-λ induces ISG expression and inhibits HCV replication exclusively through a STAT1- and STAT2-dependent pathway.
authors.affiliation: Department of Genome Science and Microbiology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.|Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Yamauchi
authors.affiliation: Department of Genome Science and Microbiology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.|Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Department of Genome Science and Microbiology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.|Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Chihara
authors.affiliation: Department of Genome Science and Microbiology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.|Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Honjoh
authors.affiliation: Department of Genome Science and Microbiology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.|Department of Otorhinolaryngology Head and Neck Surgery, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Genome Science and Microbiology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Hatsumi
authors.initials: H
authors.lastname: Yoshiki
authors.affiliation: Division of Microbiology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Hak
authors.initials: H
authors.lastname: Hotta
authors.affiliation: Department of Genome Science and Microbiology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.|Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Kiyonao
authors.initials: K
authors.lastname: Sada
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology; D004261:DNA Replication / Q000235:genetics; D016174:Hepacivirus / Q000235:genetics* / Q000472:pathogenicity; D006526:Hepatitis C / Q000235:genetics / Q000473:pathology / Q000821:virology; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D016898:Interferon-alpha / Q000235:genetics*; D007371:Interferon-gamma / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics*; D050795:STAT2 Transcription Factor / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D012367:RNA, Viral; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D007371:Interferon-gamma