Role of WNT/GSK-3β Signaling in the Pathogenesis of Influenza

Influenza virus A infections cause highly contagious, severe respiratory diseases that can be fatal. This virus is an enveloped, segmented, negative stranded RNA virus that belongs to the family Orthomyxoviridae. Infections with influenza A viruses induce a variety of intracellular signaling and gene expression events. Intracellular signaling events include pathways that could be antiviral or proviral in nature. Recent research has identified some of these pathways: MAPK signaling, NF-kappaB signaling, PI3K/AKT signaling and Wnt singaling pathways.The Wnt signalling pathway is a complex signaling pathway that is involved in cell migration, maintenance of stem cells in many tissues, epithelial-mesenchymal interactions and cell adhesion. Wnt ligands bind to and signal via their transmembrane receptors belonging to the Frizzled (FZD) family, which then activates Disheveled family proteins (DVL). In the absence of Wnt ligands, Axin and APC form a cytoplasmic multi-protein complex with β-catenin which initiates phosphorylation by GSK-3beta and CK-1 subsequently leading to the phosphorylation and degradation of β-catenin. Wnt binding results in the release and nuclear translocation of β-catenin which then activates transcription of target genes as a complex with other transcriptional activators and co-activators such as TCF/LEF and p160.Studies show that in influenza infected cells, the Wnt signaling pathway is triggered leading to a β-catenin/TCF-induced IFN production. A number of Wnt pathway molecules are found to either be regulated by influenza virus A proteins or physically interact with influenza A proteins. NS1 downregulates expression of FZD, and DVL family proteins bind to PA, PB1, PB2, M1 and M2 and NP. The p160 transcriptional co-activator family of proteins as well as the APC-interacting ubiquitin ligase SIAH1 bind NP, PB1, PB2 and PA. Other studies show that influenza virus infection is reduced in the presence of siRNA specific to GSK-3β, providing strong evidence for a role of WNT/GSK-3β signaling pathway in influenza infections.