Genome-wide RNAi Screen Reveals a New Role of a WNT/CTNNB1 Signaling Pathway as Negative Regulator of Virus-induced Innate Immune Responses

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. © 2013 baril et al.