Abstract
The rapid activation of the type I interferon (IFN) antiviral innate immune response relies on ubiquitously expressed RNA and DNA sensors. Once engaged, these nucleotide-sensing receptors use distinct signaling modules for the rapid and robust activation of mitogen-activated protein kinases (MAPKs), the IκB kinase (IKK) complex, and the IKK-related kinases IKKε and TANK-binding kinase 1 (TBK1), leading to the subsequent activation of the activator protein 1 (AP1), nuclear factor-kappa B (NF-κB), and IFN regulatory factor 3 (IRF3) transcription factors, respectively. They, in turn, induce immunomodulatory genes, allowing for a rapid antiviral cellular response. Unlike the MAPKs, the IKK complex and the IKK-related kinases, ubiquitously expressed glycogen synthase kinase 3 (GSK-3) α and β isoforms are active in unstimulated resting cells and are involved in the constitutive turnover of β-catenin, a transcriptional coactivator involved in cell proliferation, differentiation, and lineage commitment. Interestingly, studies have demonstrated the regulatory roles of both GSK-3 and β-catenin in type I IFN antiviral innate immune response, particularly affecting the activation of IRF3. In this review, we summarize current knowledge on the mechanisms by which GSK-3 and β-catenin control the antiviral innate immune response to RNA and DNA virus infections.
Highlights
In mammals, glycogen synthase kinase-3 (GSK-3) refers to two paralogous genes, GSK3A on chromosome 19 and GSK3B on chromosome 3, that generate two related protein isoforms, GSK-3α and GSK-3β [1,2]
In response to specific inflammatory triggers, GSK-3β interacts with the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and undergoes K63-linked polyubiquitination at Lys183, a modification required for the production of proinflammatory cytokines [30]
We showed that the deletion of the phosphodegron motif of β-catenin decreases the DNA binding activity of IFN regulatory factor 3 (IRF3) and the antiviral innate immune response following Sendai virus (SeV) and vesicular stomatitis virus (VSV)
Summary
Glycogen synthase kinase-3 (GSK-3) refers to two paralogous genes, GSK3A on chromosome 19 and GSK3B on chromosome 3, that generate two related protein isoforms, GSK-3α and GSK-3β [1,2]. In response to specific inflammatory triggers, GSK-3β interacts with the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and undergoes K63-linked polyubiquitination at Lys183, a modification required for the production of proinflammatory cytokines [30] Both isoforms play various roles in several signaling pathways including the Wnt, Ras/MAPK, cyclic AMP, transforming growth factor-β/activin, Notch, Hedgehog, phosphatidylinositol-3 kinase (PI3K), jun kinase/stress-activated protein kinase (JNK/SAPK), nuclear factor-kappa B (NF-κB), and the Janus kinase/signal transducer and activator of transcription (JAK/STAT). Along with CBP/p300, they induce a gene network involved in cell proliferation, differentiation, and lineage commitment Another mechanism of β-catenin nuclear translocation is the growth factor (GF) receptor (GFR)-mediated, AKT-dependent phosphorylation of β-catenin at Ser552 or its deacetylation by HDAC6 at Lys.
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