Detection of intracellular DNA by the cGAS-STING pathway activates a type I interferon-mediated innate immune response that protects from virus infection. Whether there are additional DNA sensing pathways, and how such pathways might function, remains controversial. We show here that humans-but not laboratory mice-have a second, potent, STING-independent DNA sensing pathway (SIDSP). We identify human DNA-dependent protein kinase (DNA-PK) as the sensor of this pathway and demonstrate that DNA-PK activity drives a robust and broad antiviral response. We show that the E1A oncoprotein of human adenovirus 5 and the ICP0 protein of herpes simplex virus 1 block this response. We found heat shock protein HSPA8/HSC70 as a target for inducible phosphorylation in the DNA-PK antiviral pathway. Last, we demonstrate that DNA damage and detection of foreign DNA trigger distinct modalities of DNA-PK activity. These findings reveal the existence, sensor, a specific downstream target, and viral antagonists of a SIDSP in human cells.

中文翻译：

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人DNA-PK激活了独立于STING的DNA感应途径。

通过cGAS-STING途径检测细胞内DNA可激活I型干扰素介导的先天免疫应答，从而防止病毒感染。是否还有其他的DNA传感途径，以及这种途径如何发挥作用，仍存在争议。我们在这里显示，人类（而非实验室小鼠）具有第二条有效的，独立于STING的DNA传感途径（SIDSP）。我们确定人类DNA依赖性蛋白激酶（DNA-PK）作为此途径的传感器，并证明DNA-PK活性驱动强大而广泛的抗病毒反应。我们显示，人类腺病毒5的E1A癌蛋白和单纯疱疹病毒1的ICP0蛋白可阻止此反应。我们发现热激蛋白HSPA8 / HSC70作为DNA-PK抗病毒途径中诱导型磷酸化的靶标。持续，我们证明了DNA损伤和外源DNA的检测触发了DNA-PK活性的不同模式。这些发现揭示了人细胞中SIDSP的存在，传感器，特定的下游靶标和病毒拮抗剂。