β-Catenin Upregulates the Constitutive and Virus-Induced Transcriptional Capacity of the Interferon Beta Promoter through T-Cell Factor Binding Sites

Abstract

. Rapid upregulation of IFN-␤ gene expression occurs after recognition of viral nucleic acids by pattern recognition receptors (PRRs) consisting of either cytosolic receptors, such as retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA-5), or membrane-associated Toll-like receptors, such as Toll-like receptor 3 (TLR3) (3). After sensing single-or doublestranded RNA of viral origin, these receptors activate signaling pathways, implicating the phosphorylation and nuclear translocation of several transcription factors, among which is interferon regulatory factor 3 (IRF3), rapidly leading downstream to a robust activation of expression of the IFN-␤ gene. After being secreted, the IFN-␤ protein binds to the type I interferon receptor and triggers the JAK-STAT1/2 signal transduction pathway. This pathway leads to the activation and inhibition of the expression of a large set of genes that constitute the type I IFN response mounted to antagonize viral infection at different levels (4).Mice lacking IFN-␤ (5) or the subunit of the type I interferon receptor (6, 7) are highly susceptible to viral infections. They succumb to sublethal doses of a variety of viruses, thus confirming the main role of IFN-␤ in the establishment of an innate antiviral response. However, beyond the antiviral response, IFN-␤ affects a wide range of other biological functions; for the most part, these are related to modulation of the immune (innate and adaptive) and inflammatory responses as well as to cell proliferation and differentiation. Even though IFN-␤ has been described to have an anti-inflammatory benefit, it has also been implicated in the development of several inflammatory and autoimmune diseases (8-10). Hence, the beneficial or detrimental outcome of IFN-␤ expression for the organism depends on the timing and kinetics of IFN-␤ synthesis and the amount of IFN-␤ being synthesized (11,12). If a marked activation of IFN-␤ gene expression is required to efficiently set up the appropriate response to an external aggression, such as virus infection, this response needs to be adjusted in order to limit its pathological side effects.As expected for a gene with pleiotropic functions, its transcriptional state is regulated at different levels. At the cellular level, only a stochastic fraction of the infected cells produces 14) as a way to avoid an exacerbated and uncontrolled IFN response. At the nuclear level, one IFN-␤ allele localizes within interchromosomal regions rich in NF-B DNA binding sites before and after infection (15), whereas the other allele localizes next to pericentromeric heterochromatin (PCH) clusters in the absence of infection and dissociates from PCH clusters during infection (16). The monoallelic characteristic of these particular subnuclear localizations suggests that a yet undeciphered regulatory mechanism exists at the chromosome level. Finally, at the promoter level, the coordinated action of several transcription factors and chromatin-remodeling complexes (17-21) regulates the...

Roles of GSK-3 and β-Catenin in Antiviral Innate Immune Sensing of Nucleic Acids

“…We and others have observed that when this form accumulates in response to the use of GSK-3 inhibitors, in the presence of Wnt ligands, or through β-catenin overexpression, it negatively affects the type I IFN response in cells following RLR stimulation [88][89][90]. However, other groups have reported the opposite in response to RNA viruses, including influenza A virus, human immunodeficiency virus (HIV), bovine parainfluenza virus type 3, and Rift Valley fever virus [40,81,82,91,92].…”

“…Due to the paucity of these studies, the working models have sometimes been in contradiction. However, pictures are emerging where (1) GSK-3 operates at the level of β-catenin [74] and/or TBK1 [75,76]; and (2) β-catenin acts via the classical holocomplex formed by IRF3 and CBP/p300 [74,[77][78][79][80][81] or TCF [82] to regulate the production of type I IFNs (Figure 3). receptor-associated factors (TRAFs) to polymerized MAVS results in the activation of the constitutively expressed protein kinase TANK-binding kinase 1 (TBK1) and its inducible homologue IKKi (or IKKε).…”

“…Arrows represent activation, whereas blocking arrows signify inhibition. Though recently demonstrated to be involved in the TCF-dependent basal production of IFNβ [82], the first study implying a role of β-catenin in virus-induced IFNB1 transcription came with the discovery of the role of LRRFIP1, a β-catenin and RNA-binding protein acting in parallel to the RLR-TBK1-IRF3 pathway, in the production of type I IFN [78]. Once engaged by nucleic acids, LRRFIP1 is found in immunocomplexes containing β-catenin, where it enables its phosphorylation at Ser552 and accumulation in the nucleus.…”

“…Indeed, N-terminally phosphorylated β-catenin has essential roles in microtubule organization at the centrosomes [95,96], cell adhesion, and migration [97,98], maintaining neuroepithelial integrity in developing midbrain [99], promoting neuronal excitability [100], and enhancing the transcriptional activity of the β-catenin/TCF4 complex [101]. It could be proposed that the "active" non-phosphorylated form of β-catenin is required for the replication of viral constituents [102], as well as constitutive-basal IFNβ production [82]. Nevertheless, the GSK-3-modified version of β-catenin would be required for an optimal antiviral immune response.…”

Regulation of Wnt/β-catenin signaling by herpesviruses

“…Data from Marcato et al[82] suggests that the TCF/β-catenin complex is instrumental in mounting an effective antiviral response. They linked two observations, namely, that IFN-β is needed during the innate antiviral response and that murine models lacking IFN-β are susceptible to viral infections.…”