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.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Carrier Proteins / immunology
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Carrier Proteins / metabolism
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Cell Line
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DEAD Box Protein 58
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DEAD-box RNA Helicases / immunology
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DEAD-box RNA Helicases / metabolism
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Female
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology
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Genome-Wide Association Study
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Glycoproteins / immunology*
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Glycoproteins / metabolism
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Humans
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Immunity, Innate*
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Interferon-beta / immunology
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Interferon-beta / metabolism
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Intracellular Signaling Peptides and Proteins / immunology*
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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RNA Interference
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RNA-Binding Proteins
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Receptors, Immunologic
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Respirovirus Infections / immunology*
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Respirovirus Infections / metabolism
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Respirovirus Infections / pathology
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Sendai virus / immunology*
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Sendai virus / metabolism
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Wnt Proteins / immunology*
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Wnt Proteins / metabolism
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Wnt Signaling Pathway / immunology*
Substances
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Adaptor Proteins, Signal Transducing
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CTNNBIP1 protein, human
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Carrier Proteins
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Glycoproteins
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IFIT1 protein, human
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Intracellular Signaling Peptides and Proteins
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RNA-Binding Proteins
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Receptors, Immunologic
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WNT2B protein, human
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WNT9B protein, human
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Wnt Proteins
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Interferon-beta
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RIGI protein, human
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DEAD Box Protein 58
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DEAD-box RNA Helicases