β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein

Abstract

The cGAS/STING-mediated DNA-sensing signaling pathway is crucial for interferon (IFN) production and host antiviral responses. Herpes simplex virus I (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. Here, we demonstrate that the highly conserved β-catenin protein in the Wnt signaling pathway is an important factor to enhance the transcription of type I interferon (IFN-I) in the cGAS/STING signaling pathway, and the production of IFN-I mediated by β-catenin was antagonized by HSV-1 US3 protein via its kinase activity. Infection by US3-deficienct HSV-1 and its kinase-dead variants failed to downregulate IFN-I and IFN-stimulated gene (ISG) production induced by β-catenin. Consistent with this, absence of β-catenin enhanced the replication of US3-deficienct HSV-1, but not wild-type HSV-1. The underlying mechanism was the interaction of US3 with β-catenin and its hyperphosphorylation of β-catenin at Thr556 to block its nuclear translocation. For the first time, HSV-1 US3 has been shown to inhibit IFN-I production through hyperphosphorylation of β-catenin and to subvert host antiviral innate immunity. IMPORTANCE Although increasing evidence has demonstrated that HSV-1 subverts host immune responses and establishes lifelong latent infection, the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity, especially the cGAS/STING-mediated cellular DNA-sensing signaling pathway, have not been fully explored. Here, we show that β-catenin promotes cGAS/STING-mediated activation of the IFN pathway, which is important for cellular innate immune responses and intrinsic resistance to DNA virus infection. The protein kinase US3 antagonizes the production of IFN by targeting β-catenin via its kinase activity. The findings in this study reveal a novel mechanism for HSV-1 to evade host antiviral immunity and add new knowledge to help in understanding the interaction between the host and HSV-1 infection.

Herpes Simplex Virus Type 1 Interactions with the Interferon System

“…Alternatively, activation of TBK1 by STING can activate the NF-κB pathway [ 79 ] ( Figure 1 ). Recently, it has been shown that β-catenin is an essential component of the cGAS-STING pathway and blocking the nuclear translocation of β-catenin reduces type I IFN production [ 80 ]. While cGAS is primarily cytoplasmic, it is partially located in the nucleus of fibroblasts and keratinocytes and there is evidence it plays a role in stabilizing IFI16, another viral DNA sensor (described below) [ 81 , 82 ].…”

“…pUS3, in conjunction with pUL13 also dampens the IFNγ response by inhibiting the phosphorylation of IFNGR1, a requirement for complete activation of the IFNGR receptor [ 203 ]. Recent evidence has shown that pUS3 also inhibits the actions of β-catenin following activation of the cGAS-STING pathway by blocking the nuclear translocation of β-catenin in mouse fibroblasts, further dampening the type I IFN response [ 80 ].…”

Hepatitis B virus X protein promotes vimentin expression via LIM and SH3 domain protein 1 to facilitate epithelial-mesenchymal transition and hepatocarcinogenesis

“…The culture for HepG2, Huh7, and HEK293T cells was followed as described [ 26 – 28 ]. According to the manual, the cells were transfected with target plasmids with LipoMax DNA transfection reagent.…”

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

“…At the moment, the cross talk that may exist between GSK-3/β-catenin pathways and the effectors described above were documented at the level of the recruitment of GSK-3 to TBK1 in herpes simplex virus (HSV-1)-infected cells [76]. Recently, the requirement of β-catenin in the cGAS/STING mediated activation of the IFN pathway was shown in a reporter assay [119]. This could likely happen through the binding of p-β-catenin Ser552 with IRF3 promoter in association with TCF4, as reported following STING activation in Toxoplasma gondii infection [120].…”

“…This could likely happen through the binding of p-β-catenin Ser552 with IRF3 promoter in association with TCF4, as reported following STING activation in Toxoplasma gondii infection [120]. It is interesting to note, however, that viral interference inhibiting the functions of both GSK-3 and β-catenin has been observed with many DNA viruses-encoded proteins including the hepatitis B virus (HBV) X protein [121], the Epstein-Barr virus (EBV) LMP2A [122,123], the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus (KSHV) [124], and the US3 protein from HSV-1 [119]. In addition to viral interference antagonizing the GSK-3/β-catenin pathways, other DNA viruses, such as human cytomegalovirus, use GSK-3 at their advantage to induce the degradation of SPOC1 (survival time-associated PHD (plant homeodomain) finger protein in ovarian cancer 1), a transcriptional coregulator involved in the inhibition of viral immediate-early (IE) gene expression [125].…”