Genome-wide RNAi screen reveals a novel role of WNT/CTNNB1 signaling pathway in regulation of innate antiviral responses (67.7)

Abstract

Abstract To identify new regulators of innate antiviral immunity, we completed the first genome-wide gene silencing screen assessing the transcriptional response at the interferon-β gene (IFNB1) promoter following Sendai virus (SeV) infection. We identified 237 potential modulator genes for which negative or positive actions of gene products were mapped to the different steps of the antiviral responses from virus sensing, signal propagation/amplification up to the feedback regulation. In the present study, we will report on specific proteins that promote IFNB1 expression and innate antiviral response. The functional genomics screen uncovers a novel link between WNT family members and innate antiviral immunity. We show that virus-induced secretion of WNT2B and WNT9B down regulates IFNB1 and ISG56 expression in a β-catenin (CTNNB1)-dependent mechanism. The antiviral response is drastically reduced by GSK3 inhibitors but completely restored in CTNNB1 knockdown cells. The findings confirm a novel regulation of the innate antiviral response by a canonical WNT/GSK3/CTNNB1 pathway in a negative feedback mechanism. The study identifies novel avenues for therapeutically regulating innate immunity for effective treatment of viral infection and prevention of excessive response in autoimmune diseases.