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

102 Citations (Scopus)

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

Fingerprint

Viruses
Interferons
DNA Damage
DNA
Tyrosine
Interferon-Stimulated Gene Factor 3
Proteins
Apoptosis Regulatory Proteins
Phosphorylation
Viral Genes
Response Elements
Viral Proteins
Down-Regulation
Genes
Neoplasms

Keywords

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

ASJC Scopus subject areas

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

Cite this

Cheon, H., Holvey-Bates, E. G., Schoggins, J. W., Forster, S., Hertzog, P., Imanaka, N., ... 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

IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. / Cheon, Hyeonjoo; Holvey-Bates, Elise G.; Schoggins, John W.; Forster, Samuel; Hertzog, Paul; Imanaka, Naoko; Rice, Charles M.; Jackson, Mark W.; Junk, Damian J.; Stark, George R.

In: EMBO Journal, Vol. 32, No. 20, 16.10.2013, p. 2751-2763.

Research output: Contribution to journalArticle

Cheon, H, Holvey-Bates, EG, Schoggins, JW, Forster, S, Hertzog, P, Imanaka, N, Rice, CM, Jackson, MW, Junk, DJ & Stark, GR 2013, 'IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage', EMBO Journal, vol. 32, no. 20, pp. 2751-2763. https://doi.org/10.1038/emboj.2013.203
Cheon, Hyeonjoo ; Holvey-Bates, Elise G. ; Schoggins, John W. ; Forster, Samuel ; Hertzog, Paul ; Imanaka, Naoko ; Rice, Charles M. ; Jackson, Mark W. ; Junk, Damian J. ; Stark, George R. / IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. In: EMBO Journal. 2013 ; Vol. 32, No. 20. pp. 2751-2763.
@article{033951fd099341f5ac76ef438359c4fc,
title = "IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage",
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.",
keywords = "anti-viral genes, DNA damage resistance, interferon-β, unphosphorylated interferon-stimulated gene factor 3 (U-ISGF3)",
author = "Hyeonjoo Cheon and Holvey-Bates, {Elise G.} and Schoggins, {John W.} and Samuel Forster and Paul Hertzog and Naoko Imanaka and Rice, {Charles M.} and Jackson, {Mark W.} and Junk, {Damian J.} and Stark, {George R.}",
year = "2013",
month = "10",
day = "16",
doi = "10.1038/emboj.2013.203",
language = "English (US)",
volume = "32",
pages = "2751--2763",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "20",

}

TY - JOUR

T1 - IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage

AU - Cheon, Hyeonjoo

AU - Holvey-Bates, Elise G.

AU - Schoggins, John W.

AU - Forster, Samuel

AU - Hertzog, Paul

AU - Imanaka, Naoko

AU - Rice, Charles M.

AU - Jackson, Mark W.

AU - Junk, Damian J.

AU - Stark, George R.

PY - 2013/10/16

Y1 - 2013/10/16

N2 - 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.

AB - 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.

KW - anti-viral genes

KW - DNA damage resistance

KW - interferon-β

KW - unphosphorylated interferon-stimulated gene factor 3 (U-ISGF3)

UR - http://www.scopus.com/inward/record.url?scp=84885869823&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885869823&partnerID=8YFLogxK

U2 - 10.1038/emboj.2013.203

DO - 10.1038/emboj.2013.203

M3 - Article

VL - 32

SP - 2751

EP - 2763

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 20

ER -