Zhang Dandan, Su Chenhe, Zheng Chunfu
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
J Virol. 2016 May 27;90(12):5824-5829. doi: 10.1128/JVI.00186-16. Print 2016 Jun 15.
The interferon (IFN)-mediated antiviral response is a central aspect of host defense; however, viruses have evolved multiple strategies to counteract IFN-mediated responses in order to successfully infect the host. Herpes simplex virus 1 (HSV-1), a typical human-restricted DNA virus, is capable of counteracting host immune responses via several distinct viral proteins, thus establishing a lifelong latent infection. In this study, we demonstrate that the VP24 protein, a serine protease of HSV-1 essential for the formation and maturation of capsids, is a novel antagonist of the beta interferon (IFN-β) pathway. Here, VP24 was shown for the first time to dampen interferon stimulatory DNA (ISD)-triggered IFN-β production and inhibit IFN-β promoter activation induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) and by STING, respectively. Further study demonstrated that ectopic expression of VP24 selectively blocked IFN regulatory factor 3 (IRF3) but not NF-κB promoter activation. In addition, VP24 was demonstrated to downregulate ISD-induced phosphorylation and dimerization of IRF3 during HSV-1 infection with a VP24 stable knockdown human foreskin fibroblast cell line. The underlying molecular mechanism is that VP24 abrogates the interaction between TANK-binding kinase 1 (TBK1) and IRF3, hence impairing IRF3 activation. These results illustrate that VP24 is able to block the production of IFN-β by inhibiting IRF3 activation, which may represent a critical adaptation to enable viral effective replication within the host.
This study demonstrated that HSV-1 protein VP24 could inhibit IFN-β production and promoter activation triggered by ISD, cGAS and STING and by STING, respectively. VP24 selectively blocked IRF3 promoter activation and ISD-induced phosphorylation and dimerization of IRF3 without affecting the NF-κB promoter activation during viral infection. VP24 also inhibited IRF3 activation by impeding the interaction between TBK1 and IRF3 during viral infection. This study provides new insights into the immune evasion mediated by HSV-1 and identifies VP24 as a crucial effector for HSV-1 to evade the host DNA-sensing signal pathway.
干扰素（IFN）介导的抗病毒反应是宿主防御的核心方面；然而，病毒已经进化出多种策略来对抗IFN介导的反应，以便成功感染宿主。单纯疱疹病毒1型（HSV-1）是一种典型的人类限制性DNA病毒，能够通过几种不同的病毒蛋白对抗宿主免疫反应，从而建立终身潜伏感染。在本研究中，我们证明VP24蛋白是HSV-1的一种丝氨酸蛋白酶，对衣壳的形成和成熟至关重要，它是β干扰素（IFN-β）途径的一种新型拮抗剂。在此，首次表明VP24可抑制干扰素刺激DNA（ISD）触发的IFN-β产生，并分别抑制由环磷酸鸟苷-腺苷合成酶（cGAS）和干扰素基因刺激物（STING）以及由STING诱导的IFN-β启动子激活。进一步研究表明，VP24的异位表达选择性地阻断了干扰素调节因子3（IRF3）的启动子激活，但不影响NF-κB启动子激活。此外，在用VP24稳定敲低的人包皮成纤维细胞系进行HSV-1感染期间，VP24被证明可下调ISD诱导的IRF3磷酸化和二聚化。潜在的分子机制是VP24消除了TANK结合激酶1（TBK1）与IRF3之间的相互作用，从而损害了IRF3的激活。这些结果表明，VP24能够通过抑制IRF3激活来阻断IFN-β的产生，这可能是病毒在宿主体内有效复制的关键适应性表现。
本研究表明，HSV-1蛋白VP24可分别抑制由ISD、cGAS和STING以及由STING触发的IFN-β产生和启动子激活。在病毒感染期间，VP24选择性地阻断IRF3启动子激活以及ISD诱导的IRF3磷酸化和二聚化，而不影响NF-κB启动子激活。VP24还通过在病毒感染期间阻碍TBK1与IRF3之间的相互作用来抑制IRF3激活。本研究为HSV-1介导的免疫逃避提供了新的见解，并确定VP24是HSV-1逃避宿主DNA传感信号通路的关键效应因子。
