Genome-wide RNAi screen reveals a new role of a WNT/CTNNB1 signaling pathway as negative regulator of virus-induced innate immune responses

• Published in: PLoS pathogens 2013-06, Vol.9 (6), p.e1003416-e1003416
• Main Authors: Baril, Martin, Es-Saad, Salwa, Chatel-Chaix, Laurent, Fink, Karin, Pham, Tram, Raymond, Valérie-Ann, Audette, Karine, Guenier, Anne-Sophie, Duchaine, Jean, Servant, Marc, Bilodeau, Marc, Cohen, Eric, Grandvaux, Nathalie, Lamarre, Daniel
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Biology; Carrier Proteins - immunology; Carrier Proteins - metabolism; Cell Line; Cellular signal transduction; Cytokines; DEAD Box Protein 58; DEAD-box RNA Helicases - immunology; DEAD-box RNA Helicases - metabolism; Female; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; Genetic aspects; Genome-wide association studies; Genome-Wide Association Study; Glycoproteins - immunology; Glycoproteins - metabolism; Host-parasite relationships; Humans; Immune response; Immune system; Immunity, Innate; Interferon-beta - immunology; Interferon-beta - metabolism; Intracellular Signaling Peptides and Proteins - immunology; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Male; Medical research; Medicine; Receptors, Immunologic; Respirovirus Infections - immunology; Respirovirus Infections - metabolism; Respirovirus Infections - pathology; RNA Interference; RNA-Binding Proteins; Sendai virus - immunology; Sendai virus - metabolism; Viral infections; Wnt Proteins - immunology; Wnt Proteins - metabolism; Wnt Signaling Pathway - immunology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003416

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.