Research ArticleInnate Immunity

ETV7 limits antiviral gene expression and control of influenza viruses

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Science Signaling  13 Jul 2021:
Vol. 14, Issue 691, eabe1194
DOI: 10.1126/scisignal.abe1194

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Controlling the antiviral interferon response

Type I interferons initiate the changes in gene expression that are critical for fighting viral infections. However, restraining the type I interferon response is equally important for avoiding pathology resulting from inflammation. Froggatt et al. identified an interferon-stimulated gene (ISG) that encodes the transcription factor ETV7, which suppressed the expression of other ISGs, including those critical for controlling influenza viruses in lung epithelial cells. These results suggest that regulatory factors such as ETV7 may regulate the balance between control of viral infection and the excessive inflammation associated with severe viral disease.


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.

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