A molecular switch from STAT2-IRF9 to ISGF3 underlies interferon-induced gene transcription

Ekaterini Platanitis, Duygu Demiroz, Anja Schneller, Katrin Fischer, Christophe Capelle, Markus Hartl, Thomas Gossenreiter, Mathias Müller, Maria Novatchkova and Thomas Decker ()
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Ekaterini Platanitis: University of Vienna
Duygu Demiroz: University of Vienna
Anja Schneller: University of Vienna
Katrin Fischer: University of Vienna
Christophe Capelle: University of Vienna
Markus Hartl: University of Vienna
Thomas Gossenreiter: University of Vienna
Mathias Müller: University of Veterinary Medicine Vienna
Maria Novatchkova: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
Thomas Decker: University of Vienna

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Cells maintain the balance between homeostasis and inflammation by adapting and integrating the activity of intracellular signaling cascades, including the JAK-STAT pathway. Our understanding of how a tailored switch from homeostasis to a strong receptor-dependent response is coordinated remains limited. Here, we use an integrated transcriptomic and proteomic approach to analyze transcription-factor binding, gene expression and in vivo proximity-dependent labelling of proteins in living cells under homeostatic and interferon (IFN)-induced conditions. We show that interferons (IFN) switch murine macrophages from resting-state to induced gene expression by alternating subunits of transcription factor ISGF3. Whereas preformed STAT2-IRF9 complexes control basal expression of IFN-induced genes (ISG), both type I IFN and IFN-γ cause promoter binding of a complete ISGF3 complex containing STAT1, STAT2 and IRF9. In contrast to the dogmatic view of ISGF3 formation in the cytoplasm, our results suggest a model wherein the assembly of the ISGF3 complex occurs on DNA.

Date: 2019
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DOI: 10.1038/s41467-019-10970-y

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