Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I.
Virus-responsive signaling pathways that induce alpha/beta interferon production and engage intracellular immune defenses influence the outcome of many viral infections. The processes that trigger these defenses and their effect upon host permissiveness for specific viral pathogens are not well understood. We show that structured hepatitis C virus (HCV) genomic RNA activates interferon regulatory factor 3 (IRF3), thereby inducing interferon in cultured cells. This response is absent in cells selected for permissiveness for HCV RNA replication. Studies including genetic complementation revealed that permissiveness is due to mutational inactivation of RIG-I, an interferon-inducible cellular DExD/H box RNA helicase. Its helicase domain binds HCV RNA and transduces the activation signal for IRF3 by its caspase recruiting domain homolog. RIG-I is thus a pathogen receptor that regulates cellular permissiveness to HCV replication and, as an interferon-responsive gene, may play a key role in interferon-based therapies for the treatment of HCV infection.
Sumpter
Rhea
R
Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9048, USA.
Loo
Yueh-Ming
YM
Foy
Eileen
E
Li
Kui
K
Yoneyama
Mitsutoshi
M
Fujita
Takashi
T
Lemon
Stanley M
SM
Gale
Michael
M
D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D004268:DNA-Binding Proteins / Q000378:metabolism; D005816:Genetic Complementation Test; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D020365:RNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis*; D011971:Receptors, Immunologic; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014779:Virus Replication
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011971:Receptors, Immunologic; D014157:Transcription Factors; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D020365:RNA Helicases