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

Nat Commun. 2019 Jul 2;10(1):2921. doi: 10.1038/s41467-019-10970-y.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Gene Expression Regulation*
  • Humans
  • Interferon-Stimulated Gene Factor 3 / genetics
  • Interferon-Stimulated Gene Factor 3 / metabolism*
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism*
  • Interferons / metabolism*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Promoter Regions, Genetic
  • RAW 264.7 Cells
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • STAT2 Transcription Factor / genetics
  • STAT2 Transcription Factor / metabolism*
  • Transcription, Genetic


  • IRF9 protein, mouse
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • STAT1 Transcription Factor
  • STAT2 Transcription Factor
  • Interferons