IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage

Hyeonjoo Cheon, Elise G. Holvey-Bates, John W. Schoggins, Samuel Forster, Paul Hertzog, Naoko Imanaka, Charles M. Rice, Mark W. Jackson, Damian J. Junk, George R. Stark

Research output: Contribution to journalArticle

121 Scopus citations

Abstract

A single high dose of interferon-β (IFNβ) activates powerful cellular responses, in which many anti-viral, pro-apoptotic, and anti-proliferative proteins are highly expressed. Since some of these proteins are deleterious, cells downregulate this initial response rapidly. However, the expression of many anti-viral proteins that do no harm is sustained, prolonging a substantial part of the initial anti-viral response for days and also providing resistance to DNA damage. While the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase, the related factor un-phosphorylated ISGF3 (U-ISGF3), formed by IFNβ-induced high levels of IRF9 and STATs 1 and 2 without tyrosine phosphorylation, drives the second prolonged response. The U-ISGF3-induced anti-viral genes that show prolonged expression are driven by distinct IFN stimulated response elements (ISREs). Continuous exposure of cells to a low level of IFNβ, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase in other IFNβ-induced proteins, and to constitutive resistance to DNA damage.

Original languageEnglish (US)
Pages (from-to)2751-2763
Number of pages13
JournalEMBO Journal
Volume32
Issue number20
DOIs
StatePublished - Oct 16 2013

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Keywords

  • DNA damage resistance
  • anti-viral genes
  • interferon-β
  • unphosphorylated interferon-stimulated gene factor 3 (U-ISGF3)

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Cheon, H., Holvey-Bates, E. G., Schoggins, J. W., Forster, S., Hertzog, P., Imanaka, N., Rice, C. M., Jackson, M. W., Junk, D. J., & Stark, G. R. (2013). IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. EMBO Journal, 32(20), 2751-2763. https://doi.org/10.1038/emboj.2013.203