title: Genome-wide RNAi screen reveals a new role of a WNT/CTNNB1 signaling pathway as negative regulator of virus-induced innate immune responses.
abstract: To identify new regulators of antiviral innate immunity, we completed the first genome-wide gene silencing screen assessing the transcriptional response at the interferon-β (IFNB1) promoter following Sendai virus (SeV) infection. We now report a novel link between WNT signaling pathway and the modulation of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-dependent innate immune responses. Here we show that secretion of WNT2B and WNT9B and stabilization of β-catenin (CTNNB1) upon virus infection negatively regulate expression of representative inducible genes IFNB1, IFIT1 and TNF in a CTNNB1-dependent effector mechanism. The antiviral response is drastically reduced by glycogen synthase kinase 3 (GSK3) inhibitors but restored in CTNNB1 knockdown cells. The findings confirm a novel regulation of antiviral innate immunity by a canonical-like WNT/CTNNB1 signaling pathway. The study identifies novel avenues for broad-spectrum antiviral targets and preventing immune-mediated diseases upon viral infection.
authors.affiliation: Institut de Recherche en Immunologie et en Cancérologie-IRIC, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Baril
authors.forename: Salwa
authors.initials: S
authors.lastname: Es-Saad
authors.forename: Laurent
authors.initials: L
authors.lastname: Chatel-Chaix
authors.forename: Karin
authors.initials: K
authors.lastname: Fink
authors.forename: Tram
authors.initials: T
authors.lastname: Pham
authors.forename: Valérie-Ann
authors.initials: VA
authors.lastname: Raymond
authors.forename: Karine
authors.initials: K
authors.lastname: Audette
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Guenier
authors.forename: Jean
authors.initials: J
authors.lastname: Duchaine
authors.forename: Marc
authors.initials: M
authors.lastname: Servant
authors.forename: Marc
authors.initials: M
authors.lastname: Bilodeau
authors.forename: Eric
authors.initials: E
authors.lastname: Cohen
authors.forename: Nathalie
authors.initials: N
authors.lastname: Grandvaux
authors.forename: Daniel
authors.initials: D
authors.lastname: Lamarre
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D055106:Genome-Wide Association Study; D006023:Glycoproteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D008297:Male; D034622:RNA Interference; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; D010253:Respirovirus Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D029082:Sendai virus / Q000276:immunology* / Q000378:metabolism; D051153:Wnt Proteins / Q000276:immunology* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C411982:CTNNBIP1 protein, human; D002352:Carrier Proteins; D006023:Glycoproteins; C484290:IFIT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; C115496:WNT2B protein, human; C449090:WNT9B protein, human; D051153:Wnt Proteins; D016899:Interferon-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases