title: Hepatitis B virus X protein impairs α-interferon signaling via up-regulation of suppressor of cytokine signaling 3 and protein phosphatase 2A.
abstract: Hepatitis B Virus (HBV) causes liver cirrhosis and hepatocellular carcinoma. Standard therapy includes treatment with interferon (IFN); however, its efficacy is limited. HBV has been reported to impair IFN signaling; however, the mechanism is unclear. Here, the relationship between HBV X protein (HBx) and IFN signaling was investigated by establishing HepG2 cells, stably expressing HBx (HepG2/HBx) via retrovirus-mediated gene transfer. Subsequently, IFN negative-regulator expression and its mechanism were studied. HepG2/HBx cells showed reduced expression of IFN-stimulated genes and expressed higher levels of suppressor of cytokine signaling 3 (SOCS3) and protein phosphatase 2A (PP2A) suppressor compared with control cells. Knockdown of SOCS3 and PP2A restored IFN sensitivity. Moreover, HepG2/HBx cells showed higher phosphorylation levels of signal transducers and activators of transcription 3 and endoplasmic reticulum stress, which are inducers of SOCS3 and PP2A, respectively. Additionally, HBx-knockdown restored IFN sensitivity in HepG2.2.15.7 cells. It was also confirmed that SOCS3 and PP2A expression levels were up-regulated in the liver of patients with HBV infection. The results of this study demonstrated that HBx impairs IFN signaling via increased expression of SOCS3 and PP2A, a novel mechanistic insight, providing a potential therapeutic target to enhance the efficiency of IFN therapy. J. Med. Virol. 89:267-275, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Tsunematsu
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Goki
authors.initials: G
authors.lastname: Suda
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Yamasaki
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Machiko
authors.initials: M
authors.lastname: Umemura
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ito
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sato
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakai
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Sho
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Morikawa
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Watashi
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.affiliation: Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
mesh_terms: D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D016898:Interferon-alpha / Q000037:antagonists & inhibitors*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D016898:Interferon-alpha; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D054648:Protein Phosphatase 2
keywords: biopsy; cytokine signaling 3; hepatitis B virus X protein; interferon signaling; protein phosphatase 2A