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

Martin Baril, Salwa Es-Saad, Laurent Chatel-Chaix, Karin Fink, Tram Pham, Valérie-Ann Raymond, Karine Audette, Anne-Sophie Guenier, Jean Duchaine, Marc Servant, Marc Bilodeau, Eric Cohen, Nathalie Grandvaux, Daniel Lamarre

Journal: PLoS pathogens 2014;9(6):e1003416

PMID: 23785285

Free Full Text on Public Library of Science View on PubMed

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.

Address: Institut de Recherche en Immunologie et en Cancérologie-IRIC, Université de Montréal, Montréal, Québec, Canada.

DOI: 10.1371/journal.ppat.1003416