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

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

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

2019
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Overview
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. A rapid cellular response to interferons (IFNs) is critical for establishing antimicrobial immunity, but how cells switch from from homeostasis to IFN signaling is not fully understood. Here, the authors provide evidence that IFNs induce gene expression by alternating subunits of transcription factor ISGF3.