Abstract
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, as insufficient levels of interferon-stimulated genes (ISGs) can lead to a failure to restrict viral spread, while excessive ISG activation results in interferon-related pathologies. While both positive and negative regulatory factors can 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 complex ISG regulatory networks remain incompletely defined. In this study, we performed a CRISPR activation screen to identify new regulators of type I IFN responses. 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 specifically targeted a subset of ISGs for regulation based on their promoter sequences. We further showed the subset of ETV7-modulated ISGs is particularly important for control of influenza viruses. Together, our data demonstrate that ETV7 is a component of the complex ISG regulatory network by controlling the expression of a subset of ISGs with a potential role in directing the interferon response against specific viruses.
Significance Interferons (IFNs) were first described in 1957 and are now known to be critical for restriction of viruses. Still, our understanding of the complex web of interactions that underlie IFN responses remains incomplete. In particular, negative regulation of interferon responses has received disproportionately less study. In this work, we performed a genome-wide overexpression screen for factors capable of suppressing IFN response signaling. We identified a DNA binding transcription factor (ETV7) that, after induction by interferon, acts to suppress a subset of IFN-stimulated genes required for control of influenza viruses. Our work highlights the importance of understanding negative IFN signaling not only with respect to the magnitude and duration of the response, but also the specificity of its antiviral effects.