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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
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IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage

HyeonJoo Cheon1, Elise G Holvey-Bates, John W Schoggins

  • 1Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

The EMBO Journal
|September 26, 2013
PubMed

Insights

A single high dose of interferon-β (IFNβ) triggers a rapid cellular response, followed by a prolonged antiviral state driven by un-phosphorylated ISGF3 (U-ISGF3). This sustained response enhances DNA damage resistance.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Biology

Background:

  • Interferon-beta (IFNβ) induces rapid cellular responses involving antiviral, pro-apoptotic, and anti-proliferative proteins.
  • Cells downregulate initial IFNβ responses due to potentially deleterious protein expression.
  • Sustained expression of non-harmful antiviral proteins prolongs IFNβ's effects and confers DNA damage resistance.

Purpose of the Study:

  • To elucidate the distinct mechanisms driving the rapid and prolonged cellular responses to interferon-beta (IFNβ).
  • To identify the transcription factors responsible for different phases of IFNβ-induced gene expression.
  • To understand how continuous low-level IFNβ exposure impacts cellular responses and DNA damage resistance.

Main Methods:

  • Analysis of protein expression patterns following high-dose IFNβ stimulation.
  • Investigation of transcription factor activity, including ISGF3 and U-ISGF3.
  • Identification of specific IFN stimulated response elements (ISREs) associated with prolonged gene expression.

Main Results:

  • A rapid IFNβ response is driven by ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2).
  • A second, prolonged response is mediated by un-phosphorylated ISGF3 (U-ISGF3), involving high levels of IRF9 and STATs 1 and 2 without tyrosine phosphorylation.
  • U-ISGF3-dependent genes with prolonged expression are regulated by distinct ISREs.
  • Continuous low-level IFNβ exposure results in sustained U-ISGF3-dependent protein expression and constitutive DNA damage resistance.

Conclusions:

  • IFNβ employs distinct transcription factor pathways (ISGF3 and U-ISGF3) to orchestrate rapid and prolonged cellular responses.
  • U-ISGF3 is critical for maintaining antiviral gene expression and conferring DNA damage resistance over extended periods.
  • The findings have implications for understanding chronic IFNβ exposure, particularly in cancer contexts, and its role in cellular defense mechanisms.

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