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.

This study was performed to identify the factors affecting prognosis of oral cancer patients. 1240 pathologically confirmed oral cancer patients were included. The sociodemographic and clinical characteristics of all patients were collected. Univariate and multivariate Cox proportional hazards models were used to assess potential prognostic factors for survival. 1240 oral cancer patients were followed up for 49235.00 person months, and the 5-year overall survival rate was 64.38%. Both univariate and multivariate Cox regression analysis indicated that Body Mass Index < 18.5 kg/m2 (vs 18.5–23.9 kg/m2), age ≥ 55 years (vs < 55 years), clinical stages of II-IV (vs stage I), and poor differentiation (vs well differentiation) were associated with worse survival of oral cancer patients. While surgery (vs non-surgery) and origin of urban area (vs rural area) were protective factors. However, no significant association was found between adjuvant therapy and survival in oral cancer patients.

Innate immunity is the first line of host defense against viral infection. After invading into the cells, pathogen-associated-molecular-patterns derived from viruses are recognized by pattern recognition receptors to activate the downstream signaling pathways to induce the production of type I interferons (IFN-I) and inflammatory cytokines, which play critical functions in the host antiviral innate immune responses. Guanylate-binding proteins (GBPs) are IFN-inducible antiviral effectors belonging to the guanosine triphosphatases family. In addition to exerting direct antiviral functions against certain viruses, a few GBPs also exhibit regulatory roles on the host antiviral innate immunity. However, our understanding of the underlying molecular mechanisms of GBPs' roles in viral infection and host antiviral innate immune signaling is still very limited. Therefore, here we present an updated overview of the functions of GBPs during viral infection and in antiviral innate immunity, and highlight discrepancies in reported findings and current challenges for future studies, which will advance our understanding of the functions of GBPs and provide a scientific and theoretical basis for the regulation of antiviral innate immunity.

Stimulator of interferon genes (STING) is a pivotal innate immune adaptor, and its functions during DNA virus infections have been extensively documented. However, its homeostatic regulation is not well understood. Our study demonstrates that Unc-93 homolog B1 (UNC93B1) is a crucial checker for STING to prevent hyperactivation. Ectopic expression of UNC93B1 attenuates IFN-β promoter activity and the transcriptions of IFN-β, ISG54, and ISG56 genes. Moreover, UNC93B1 also blocks the IRF3 nuclear translocation induced by ectopic expression of both cyclic GMP-AMP synthase (cGAS) and STING and reduces the stability of STING by facilitating its autophagy-lysosome degradation, which can be reversed by lysosome inhibitors. Mechanistically, UNC93B1 interacts with STING and suppresses STING-activated downstream signaling by delivering STING to the lysosomes for degradation, depending on its trafficking capability. UNC93B1 knockout in human embryonic kidney 293T cells facilitates IFN-β promoter activity, IFN-β, ISG54, and ISG56 transcriptions, and IRF3 nuclear translocation induced by ectopic expression of cGAS and STING. Infected with herpes simplex virus-1 (HSV-1), UNC93B1 knockdown BJ cells or primary peritoneal macrophages from Unc93b1-deficient (Unc93b1 −/− ) mice show enhanced IFN-β, ISG54, and ISG56 transcriptions, TBK1 phosphorylation, and reduced STING degradation and viral replication. In addition, Unc93b1 −/− mice exhibit higher IFN-β, ISG54, and ISG56 transcriptions and lower mortality upon HSV-1 infection in vivo. Collectively, these findings demonstrate that UNC93B1 attenuates the cGAS-STING signaling pathway by targeting STING for autophagy-lysosome degradation and provide novel insights into the function of UNC93B1 in antiviral innate immunity.