title: The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus.
abstract: Host innate recognition triggers key immune responses for viral elimination. The sensing mechanism of hepatitis B virus (HBV), a DNA virus, and the subsequent downstream signaling events remain to be fully clarified. Here we found that type III but not type I interferons are predominantly induced in human primary hepatocytes in response to HBV infection, through retinoic acid-inducible gene-I (RIG-I)-mediated sensing of the 5'-ε region of HBV pregenomic RNA. In addition, RIG-I could also counteract the interaction of HBV polymerase (P protein) with the 5'-ε region in an RNA-binding dependent manner, which consistently suppressed viral replication. Liposome-mediated delivery and vector-based expression of this ε region-derived RNA in liver abolished the HBV replication in human hepatocyte-chimeric mice. These findings identify an innate-recognition mechanism by which RIG-I dually functions as an HBV sensor activating innate signaling and to counteract viral polymerase in human hepatocytes.
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan; Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Sato
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan; Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan; Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kameyama
authors.affiliation: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: PhoenixBio Co., Ltd., Higashihiroshima, Hiroshima 739-0046, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan.
authors.forename: Shuko
authors.initials: S
authors.lastname: Murakami
authors.affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan.
authors.forename: Tsunamasa
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan.
authors.forename: Sayuki
authors.initials: S
authors.lastname: Iijima
authors.affiliation: Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Watashi
authors.affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tsutsumi
authors.affiliation: Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Akita
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Kohara
authors.affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan; Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan. Electronic address: takaoka@igm.hokudai.ac.jp.
authors.forename: Akinori
authors.initials: A
authors.lastname: Takaoka
mesh_terms: D000818:Animals; D002675:Child, Preschool; D005260:Female; D015684:Gene Products, pol / Q000037:antagonists & inhibitors*; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000276:immunology*; D022781:Hepatocytes / Q000502:physiology* / Q000637:transplantation / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons / Q000378:metabolism; D008099:Liver / Q000502:physiology* / Q000821:virology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology*; D011956:Receptors, Cell Surface; D019076:Transgenes / Q000235:genetics; D018183:Transplantation Chimera; D014779:Virus Replication / Q000235:genetics; D000097905:Roundabout Proteins
chemical_list: D015684:Gene Products, pol; D007372:Interferons; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012367:RNA, Viral; D011956:Receptors, Cell Surface; C066027:P protein, Hepatitis B virus; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins