The type I interferon (IFN) response is an important component of the innate immune response to viral infection. Precise control of IFN responses is critical because insufficient expression of IFN-stimulated genes (ISGs) can lead to a failure to restrict viral spread, whereas excessive ISG activation can result in IFN-related pathologies. Although both positive and negative regulatory factors control the magnitude and duration of IFN signaling, it is also appreciated that several ISGs regulate aspects of the IFN response themselves. In this study, we performed a CRISPR activation screen to identify previously unknown regulators of the type I IFN response. We identified the strongly induced ISG encoding ETS variant transcription factor 7 (ETV7) as a negative regulator of the type I IFN response. However, ETV7 did not uniformly suppress ISG transcription. Instead, ETV7 preferentially targeted a subset of antiviral ISGs that were particularly important for IFN-mediated control of influenza viruses. Together, our data assign a function for ETV7 as an IFN response regulator and also identify ETV7 as a potential therapeutic target to increase innate antiviral responses and enhance IFN-based antiviral therapies.

I 型干扰素 (IFN) 反应是对病毒感染的先天免疫反应的重要组成部分。精确控制 IFN 反应至关重要，因为 IFN 刺激基因 (ISG) 表达不足会导致无法限制病毒传播，而过度 ISG 激活会导致 IFN 相关病理。尽管正向和负向调节因子都控制着 IFN 信号传导的幅度和持续时间，但也可以理解，几个 ISG 本身调节 IFN 反应的各个方面。在这项研究中，我们进行了 CRISPR 激活筛选，以识别以前未知的 I 型 IFN 反应调节因子。我们将强烈诱导的 ISG 编码 ETS 变异转录因子 7 (ETV7) 确定为 I 型 IFN 反应的负调节剂。然而，ETV7 没有统一抑制 ISG 转录。相反，ETV7 优先针对对 IFN 介导的流感病毒控制特别重要的抗病毒 ISG 子集。总之，我们的数据将 ETV7 指定为 IFN 反应调节剂的功能，并将 ETV7 确定为增加先天抗病毒反应和增强基于 IFN 的抗病毒治疗的潜在治疗靶点。