The type I interferon (IFN) response is an important component of the innate immune response to viral infection. Precise control of interferon responses is critical; insufficient levels of interferon-stimulated genes (ISGs) can lead to a failure to restrict viral spread while excessive ISG activation can result in interferon-related pathologies. While both positive and negative regulatory factors control the magnitude and duration of IFN signaling, it is also appreciated that a number of ISGs regulate aspects of the interferon response themselves. However, the mechanisms underlying these ISG regulatory networks remain incompletely defined. In this study, we performed a CRISPR activation screen to identify new regulators of the type I IFN response. We identified ETS variant transcription factor 7 (ETV7), a strongly induced ISG, as a protein that acts 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 known antiviral ISGs. Further, we showed the subset of ETV7-modulated ISGs was particularly important for IFN-mediated control of some viruses including influenza viruses and SARS-CoV-2. Together, our data assign a function for ETV7 as an IFN response regulator and also identify ETV7 as a therapeutic target to increase innate responses and potentiate the efficacy of interferon-based antiviral therapies.

中文翻译：

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ETV7限制了SARS-CoV-2和流感病毒的抗病毒基因表达和控制

I型干扰素（IFN）应答是对病毒感染的固有免疫应答的重要组成部分。精确控制干扰素反应至关重要。干扰素刺激基因（ISG）水平不足会导致无法限制病毒传播，而过多的ISG激活则会导致与干扰素相关的疾病。尽管正调节因子和负调节因子均控制IFN信号的强度和持续时间，但也应理解，许多ISG自身调节干扰素反应的各个方面。但是，这些ISG监管网络的基础机制仍未完全定义。在这项研究中，我们进行了CRISPR激活筛选，以识别I型IFN反应的新调节剂。我们确定了ETS变异转录因子7（ETV7），这是一种强烈诱导的ISG，作为I型IFN反应负调节剂的蛋白质；但是，ETV7不能统一抑制ISG转录。相反，ETV7优先针对已知的抗病毒ISG的子集。此外，我们显示ETV7调节的ISG的子集对于IFN介导的某些病毒（包括流感病毒和SARS-CoV-2）的控制尤为重要。总之，我们的数据确定了ETV7作为IFN反应调节剂的功能，并且还确定ETV7为增加先天反应并增强基于干扰素的抗病毒疗法的疗效的治疗靶标。我们显示ETV7调节的ISG的子集对于IFN介导的某些病毒（包括流感病毒和SARS-CoV-2）的控制尤为重要。总之，我们的数据确定了ETV7作为IFN反应调节剂的功能，并且还确定ETV7为增加先天反应并增强基于干扰素的抗病毒疗法的疗效的治疗靶标。我们显示ETV7调节的ISG的子集对于IFN介导的某些病毒（包括流感病毒和SARS-CoV-2）的控制尤为重要。总之，我们的数据确定了ETV7作为IFN反应调节剂的功能，并且还确定ETV7为增加先天反应并增强基于干扰素的抗病毒疗法的疗效的治疗靶标。