Fine-Tuning of the RIG-I-Like Receptor/Interferon Regulatory Factor 3-Dependent Antiviral Innate Immune Response by the Glycogen Synthase Kinase 3/?-Catenin Pathway.

ABSTRACT: Induction of an antiviral innate immune response relies on pattern recognition receptors, including retinoic acid-inducible gene 1-like receptors (RLR), to detect invading pathogens, resulting in the activation of multiple latent transcription factors, including interferon regulatory factor 3 (IRF3). Upon sensing of viral RNA and DNA, IRF3 is phosphorylated and recruits coactivators to induce type I interferons (IFNs) and selected sets of IRF3-regulated IFN-stimulated genes (ISGs) such as those for ISG54 (Ifit2), ISG56 (Ifit1), and viperin (Rsad2). Here, we used wild-type, glycogen synthase kinase 3? knockout (GSK-3?(-/-)), GSK-3?(-/-), and GSK-3?/? double-knockout (DKO) embryonic stem (ES) cells, as well as GSK-3?(-/-) mouse embryonic fibroblast cells in which GSK-3? was knocked down to demonstrate that both isoforms of GSK-3, GSK-3? and GSK-3?, are required for this antiviral immune response. Moreover, the use of two selective small-molecule GSK-3 inhibitors (CHIR99021 and BIO-acetoxime) or ES cells reconstituted with the catalytically inactive versions of GSK-3 isoforms showed that GSK-3 activity is required for optimal induction of antiviral innate immunity. Mechanistically, GSK-3 isoform activation following Sendai virus infection results in phosphorylation of ?-catenin at S33/S37/T41, promoting IRF3 DNA binding and activation of IRF3-regulated ISGs. This study identifies the role of a GSK-3/?-catenin axis in antiviral innate immunity.

SUBMITTER: Khan KA 

PROVIDER: S-EPMC4525315 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature