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

Ekaterini Platanitis,Ekaterini Platanitis,Maria Novatchkova,Anja Schneller,Anja Schneller,Maria Novatchkova,Christophe Capelle,Christophe Capelle,Katrin Fischer,Markus Hartl,Markus Hartl,Duygu Demiroz,Maria Novatchkova,Thomas Decker,Thomas Decker,Thomas Gossenreiter,Thomas Gossenreiter,Katrin Fischer,Maria Novatchkova,Mathias Müller

doi:10.1038/s41467-019-10970-y

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.

Highlights

Cells maintain the balance between homeostasis and inflammation by adapting and integrating the activity of intracellular signaling cascades, including the JAK-STAT pathway
By combining ChIP-seq and transcriptome analysis, we find that basal expression of many ISGs is controlled by a preformed STAT2–interferon regulatory factor 9 (IRF9) complex, whose formation does not require signaling by the IFN-I receptor
Our study shows an important contribution of STAT2–IRF9 complexes, formed independently of IFN-I receptor signaling, to constitutive ISG expression in resting cells

Summary

Introduction

Cells maintain the balance between homeostasis and inflammation by adapting and integrating the activity of intracellular signaling cascades, including the JAK-STAT pathway. As the emergence of cell-autonomous immunity is an arms race between pathogen replication and restrictive mechanisms of the host, speed is a crucial attribute of the cellular response to IFN This is true for antimicrobial gene expression that must rapidly switch between resting-state and active-state transcription. The “revving-up” or “autocrine loop” model predicts a tight coupling between homeostatic and receptor-mediated interferon signaling and that transcriptional ISG activation in resting and activated states differs in its intensity, but abides by the same mechanism. Combining highthroughput data enabled us to reveal mechanisms by which different states of the promoter-associated transcription factor ISGF3 control the switch from homeostatic to interferoninduced gene expression

Methods

Results

Conclusion