Type I interferon (IFN-I) provides effective antiviral immunity but can exacerbate harmful inflammatory reactions and cause hematopoietic stem cell (HSC) exhaustion; therefore, IFN-I expression must be tightly controlled. While signaling mechanisms that limit IFN-I induction and function have been extensively studied, less is known about transcriptional repressors acting directly on IFN-I regulatory regions. We show that NFAT5, an activator of macrophage pro-inflammatory responses, represses Toll-like receptor 3 and virus-induced expression of IFN-I in macrophages and dendritic cells. Mice lacking NFAT5 exhibit increased IFN-I production and better control of viral burden upon LCMV infection but show exacerbated HSC activation under systemic poly(I:C)-induced inflammation. We identify IFNβ as a primary target repressed by NFAT5, which opposes the master IFN-I inducer IRF3 by binding to an evolutionarily conserved sequence in the IFNB1 enhanceosome that overlaps a key IRF site. These findings illustrate how IFN-I responses are balanced by simultaneously opposing transcription factors.
The transcription factor NFAT5 limits infection-induced type I interferon responses
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Hector Huerga Encabo, Laia Traveset, Jordi Argilaguet, Ana Angulo, Estanislao Nistal-Villán, Rahul Jaiswal, Carlos R. Escalante, Christos Gekas, Andreas Meyerhans, Jose Aramburu, Cristina López-Rodríguez; The transcription factor NFAT5 limits infection-induced type I interferon responses. J Exp Med 2 March 2020; 217 (3): e20190449. doi: https://doi.org/10.1084/jem.20190449
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