β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein
β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein
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β-连环蛋白是 cGAS/STING 信号通路所必需的，但会被 HSV-1 US3 蛋白拮抗
DOI：
10.1128/jvi.01847-19
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发表时间：
2020-03-01
影响因子：
5.4
通讯作者：
Zheng, Chunfu
中科院分区：
文献类型：
--
作者：
You, Hongjuan;Lin, Yingying;Zheng, Chunfu
cGAS/STING介导的DNA传感信号通路对于干扰素（IFN）产生和宿主抗病毒应答至关重要。单纯疱疹病毒I型（HSV-1）是一种DNA病毒，它已经进化出多种策略来逃避宿主的免疫反应。在这里，我们证明了Wnt信号通路中高度保守的β-连环蛋白是增强cGAS/STING信号通路中I型干扰素（IFN-1）转录的重要因素，并且HSV-1 US 3蛋白通过其激酶活性拮抗β-连环蛋白介导的IFN-1的产生。US 3缺陷型HSV-1及其激酶死亡型感染不能下调β-catenin诱导的IFN-1和IFN-刺激基因（ISG）的产生。与此一致，β-连环蛋白的缺失增强了US 3缺陷型HSV-1的复制，但对野生型HSV-1没有。其潜在机制是US 3与β-连环蛋白的相互作用及其在Thr 556处对β-连环蛋白的过度磷酸化以阻止其核转位。尽管越来越多的证据表明HSV-1破坏宿主免疫应答并建立终身潜伏感染，但HSV-1中断抗病毒先天免疫的分子机制，特别是cGAS/STING介导的细胞DNA传感信号通路，还没有得到充分的探索。在这里，我们表明β-连环蛋白促进cGAS/STING介导的IFN途径的激活，这对于细胞先天免疫应答和对DNA病毒感染的内在抵抗是重要的。蛋白激酶US 3通过其激酶活性靶向β-连环蛋白来拮抗IFN的产生。这项研究的发现揭示了HSV-1逃避宿主抗病毒免疫的新机制，并增加了新的知识，以帮助理解宿主与HSV-1感染之间的相互作用。
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 beta-catenin protein in the Wnt signaling pathway is an important factor to enhance the transcription of type I interferon (IFN-1) in the cGAS/STING signaling pathway, and the production of IFN-1 mediated by beta-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-1 and IFN-stimulated gene (ISG) production induced by beta-catenin. Consistent with this, absence of beta-catenin enhanced the replication of US3-deficienct HSV-1, but not wild-type HSV-1. The underlying mechanism was the interaction of US3 with beta-catenin and its hyperphosphorylation of beta-catenin at Thr556 to block its nuclear translocation. For the first time, HSV-1 US3 has been shown to inhibit IFN-1 production through hyperphosphorylation of beta-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 beta-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 beta-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.