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

• DOI: 10.1038/s41467-019-10970-y
• Publication Date: 2019-07-02T10:02:56Z
• Authors: Ekaterini Platanitis; Duygu Demiroz; Anja Schneller; Katrin Fischer; Christophe Capelle; Markus Hartl; Thomas Gossenreiter; Mathias Müller; Maria Novatchkova; Thomas Decker
• Keywords: Proteomics; Male; PROMOTER ELEMENT; Transcription, Genetic; PROTEIN; Inbred C57BL; Mice; STAT1; 106023 Molekularbiologie; STAT2 Transcription Factor/genetics; Interferon-Stimulated Gene Factor 3/genetics; 106052 Cell biology; Promoter Regions, Genetic; Innate immunity; Mice, Knockout; 106022 Mikrobiologie; 0303 health sciences; Q; Interferon-Stimulated Gene Factor 3; 106023 Molecular biology; STAT1 Transcription Factor; STAT1 Transcription Factor/genetics; 106022 Microbiology; Female; 106052 Zellbiologie; Transcription; Interferons/metabolism; EXPRESSION; COMPUTATIONAL PLATFORM; Knockout; Science; IMMUNITY; Article; Promoter Regions; 03 medical and health sciences; Genetic; Macrophages/metabolism; Animals; Humans; HEMATOPOIETIC STEM-CELLS; Transcriptomics; Macrophages; gamma Subunit/genetics; STAT2 Transcription Factor; DNA; Interferon-Stimulated Gene Factor 3, gamma Subunit; INDUCED NUCLEAR FACTORS; Mice, Inbred C57BL; Gene regulation in immune cells; RAW 264.7 Cells; Gene Expression Regulation; Interferons; RESPONSES

AbstractCells 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.