| First Author | Khan KA | Year | 2015 |
| Journal | Mol Cell Biol | Volume | 35 |
| Issue | 17 | Pages | 3029-43 |
| PubMed ID | 26100021 | Mgi Jnum | J:228237 |
| Mgi Id | MGI:5705699 | Doi | 10.1128/MCB.00344-15 |
| Citation | Khan KA, et al. (2015) Fine-Tuning of the RIG-I-Like Receptor/Interferon Regulatory Factor 3-Dependent Antiviral Innate Immune Response by the Glycogen Synthase Kinase 3/beta-Catenin Pathway. Mol Cell Biol 35(17):3029-43 |
| abstractText | 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 3alpha knockout (GSK-3alpha(-/-)), GSK-3beta(-/-), and GSK-3alpha/beta double-knockout (DKO) embryonic stem (ES) cells, as well as GSK-3beta(-/-) mouse embryonic fibroblast cells in which GSK-3alpha was knocked down to demonstrate that both isoforms of GSK-3, GSK-3alpha and GSK-3beta, 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 beta-catenin at S33/S37/T41, promoting IRF3 DNA binding and activation of IRF3-regulated ISGs. This study identifies the role of a GSK-3/beta-catenin axis in antiviral innate immunity. |
