A critical host response against viral infections entails the activation of innate immune signaling that culminates in the production of antiviral proteins. DNA viruses are sensed by the cytosolic pattern recognition receptor cyclic GMP–AMP synthase (cGAS), which initiates a signaling pathway that results in production of proinflammatory cytokines such as Interferon-β (IFN-β) and activation of the antiviral response. Precise regulation of the antiviral innate immune response is required to avoid deleterious effects of its overactivation. We previously reported that the 4EHP/GIGYF2 translational repressor complex reduces the translation of Ifnb1 mRNA, which encodes IFN-β, upon RNA viral infections. Here, we report a distinct regulatory mechanism by which 4EHP controls replication of DNA viruses by translational repression of the Cgas mRNA, which encodes the DNA viral sensor cGAS. We show that 4EHP is required for effective translational repression of Cgas mRNA triggered by miR-23a. Upon infection, 4EHP deficiency bolsters the elicited innate immune response against the diverse DNA viruses Herpes simplex virus 1 (HSV-1) and Vaccinia Virus (VacV) and concomitantly reduces their rate of replication in vitro and in vivo. This study elucidates an intrinsic regulatory mechanism of the host response to DNA viruses which may provide unique opportunities for countering viral infections.

中文翻译：

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4EHP 介导的 cGAS 翻译抑制阻碍了宿主对 DNA 病毒的免疫反应


宿主对病毒感染的关键反应需要激活先天免疫信号，最终产生抗病毒蛋白。DNA 病毒由胞质模式识别受体环状 GMP-AMP 合酶 （cGAS） 感应，该合酶启动信号通路，导致促炎细胞因子如干扰素β （IFN-β） 的产生和抗病毒反应的激活。需要精确调节抗病毒先天免疫反应，以避免其过度激活的有害影响。我们之前报道过，4EHP/GIGYF2 翻译阻遏蛋白复合物在 RNA 病毒感染后减少了编码 IFN-β 的 Ifnb1 mRNA 的翻译。在这里，我们报道了一种独特的调节机制，即 4EHP 通过编码 DNA 病毒传感器 cGAS 的 Cgas mRNA 的翻译抑制来控制 DNA 病毒的复制。我们表明 4EHP 是 miR-23a 触发的 Cgas mRNA 有效翻译抑制所必需的。感染后，4EHP 缺陷增强了针对多种 DNA 病毒单纯疱疹病毒 1 （HSV-1） 和牛痘病毒 （VacV） 引发的先天免疫反应，并同时降低了它们在体外和体内的复制速率。本研究阐明了宿主对 DNA 病毒反应的内在调节机制，这可能为对抗病毒感染提供独特的机会。