title: Fine-Tuning of the RIG-I-Like Receptor/Interferon Regulatory Factor 3-Dependent Antiviral Innate Immune Response by the Glycogen Synthase Kinase 3/β-Catenin Pathway.
abstract: Induction of an antiviral innate immune response relies on pattern recognition receptors, including retinoic acid-inducible gene 1-like receptors (RLR), to detect invading pathogens, resulting in the activation of multiple latent transcription factors, including interferon regulatory factor 3 (IRF3). Upon sensing of viral RNA and DNA, IRF3 is phosphorylated and recruits coactivators to induce type I interferons (IFNs) and selected sets of IRF3-regulated IFN-stimulated genes (ISGs) such as those for ISG54 (Ifit2), ISG56 (Ifit1), and viperin (Rsad2). Here, we used wild-type, glycogen synthase kinase 3α knockout (GSK-3α(-/-)), GSK-3β(-/-), and GSK-3α/β double-knockout (DKO) embryonic stem (ES) cells, as well as GSK-3β(-/-) mouse embryonic fibroblast cells in which GSK-3α was knocked down to demonstrate that both isoforms of GSK-3, GSK-3α and GSK-3β, are required for this antiviral immune response. Moreover, the use of two selective small-molecule GSK-3 inhibitors (CHIR99021 and BIO-acetoxime) or ES cells reconstituted with the catalytically inactive versions of GSK-3 isoforms showed that GSK-3 activity is required for optimal induction of antiviral innate immunity. Mechanistically, GSK-3 isoform activation following Sendai virus infection results in phosphorylation of β-catenin at S33/S37/T41, promoting IRF3 DNA binding and activation of IRF3-regulated ISGs. This study identifies the role of a GSK-3/β-catenin axis in antiviral innate immunity.
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Kashif Aziz
authors.initials: KA
authors.lastname: Khan
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Florence
authors.initials: F
authors.lastname: Dô
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Marineau
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Doyon
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Clément
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: James R
authors.initials: JR
authors.lastname: Woodgett
authors.affiliation: Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Doble
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada marc.servant@umontreal.ca.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Servant
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D010253:Respirovirus Infections / Q000276:immunology; D018353:Rhabdoviridae Infections / Q000276:immunology; D029082:Sendai virus / Q000276:immunology*; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases