Antiviral effects of the interferon-induced protein guanylate binding protein 1 and its interaction with the hepatitis C virus NS5B protein.
Interferons (IFNs) and the interferon-stimulated genes (ISGs) play a central role in antiviral responses against hepatitis C virus (HCV) infection. We have reported previously that ISGs, including guanylate binding protein 1 (GBP-1), interferon alpha inducible protein (IFI)-6-16, and IFI-27, inhibit HCV subgenomic replication. In this study we investigated the effects of these ISGs against HCV in cell culture and their direct molecular interaction with viral proteins. HCV replication and virus production were suppressed significantly by overexpression of GBP-1, IFI-6-16, or IFI-27. Knockdown of the individual ISGs enhanced HCV RNA replication markedly. A two-hybrid panel of molecular interaction of the ISGs with HCV proteins showed that GBP-1 bound HCV-NS5B directly. A protein truncation assay showed that the guanine binding domain of GBP-1 and the finger domain of NS5B were involved in the interaction. Binding of NS5B with GBP-1 inhibited its guanosine triphosphatase GTPase activity, which is essential for its antiviral effect. Taken together, interferon-induced GBP-1 showed antiviral activity against HCV replication.


CONCLUSIONS
Binding of the HCV-NS5B protein to GBP-1 countered the antiviral effect by inhibition of its GTPase activity. These mechanisms may contribute to resistance to innate, IFN-mediated antiviral defense and to the clinical persistence of HCV infection.
Itsui
Yasuhiro
Y
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Sakamoto
Naoya
N
Kakinuma
Sei
S
Nakagawa
Mina
M
Sekine-Osajima
Yuko
Y
Tasaka-Fujita
Megumi
M
Nishimura-Sakurai
Yuki
Y
Suda
Gouki
G
Karakama
Yuko
Y
Mishima
Kako
K
Yamamoto
Machi
M
Watanabe
Takako
T
Ueyama
Mayumi
M
Funaoka
Yusuke
Y
Azuma
Seishin
S
Watanabe
Mamoru
M
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D008565:Membrane Proteins / Q000502:physiology; D024101:Mitochondrial Proteins / Q000502:physiology; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000502:physiology*; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
D000251:Adenosine Triphosphatases; D000998:Antiviral Agents; D019204:GTP-Binding Proteins; D007372:Interferons; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017361:Viral Nonstructural Proteins; C490287:GBP1 protein, human; C406887:IFI27 protein, human; C468762:IFI6 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase