title: RIG-I is required for the inhibition of measles virus by retinoids.
abstract: Vitamin A can significantly decrease measles-associated morbidity and mortality. Vitamin A can inhibit the replication of measles virus (MeV) in vitro through an RARα- and type I interferon (IFN)-dependent mechanism. Retinoid-induced gene I (RIG-I) expression is induced by retinoids, activated by MeV RNA and is important for IFN signaling. We hypothesized that RIG-I is central to retinoid-mediated inhibition of MeV in vitro. We demonstrate that RIG-I expression is increased in cells treated with retinoids and infected with MeV. The central role of RIG-I in the retinoid-anti-MeV effect was demonstrated in the Huh-7/7.5 model; the latter cells having non-functional RIG-I. RAR-dependent retinoid signaling was required for the induction of RIG-I by retinoids and MeV. Retinoid signaling was also found to act in combination with IFN to induce high levels of RIG-I expression. RIG-I promoter activation required both retinoids and MeV, as indicated by markers of active chromatin. IRF-1 is known to be regulated by retinoids and MeV, but we found recruitment of IRF-1 to the RIG-I promoter by retinoids alone. Using luciferase expression constructs, we further demonstrated that the IRF-1 response element of RIG-I was required for RIG-I activation by retinoids or IFN. These results reveal that retinoid treatment and MeV infection induces significant RIG-I. RIG-I is required for the retinoid-MeV antiviral response. The induction is dependent on IFN, retinoids and IRF-1.
authors.affiliation: McGill University Health Center Research Institute, Department of Infectious Diseases, McGill University, Montreal, Quebec, Canada.
authors.forename: Kaitlin J
authors.initials: KJ
authors.lastname: Soye
authors.forename: Claire
authors.initials: C
authors.lastname: Trottier
authors.forename: Chris D
authors.initials: CD
authors.lastname: Richardson
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ward
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D024201:Bystander Effect / Q000187:drug effects; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D008457:Measles / Q000188:drug therapy; D008459:Measles virus / Q000187:drug effects*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011971:Receptors, Immunologic; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D050856:Interferon Regulatory Factor-1; C000607071:RARA protein, human; D011971:Receptors, Immunologic; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D014212:Tretinoin; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases