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

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

Research output: Contribution to journalArticleResearchpeer-review

103 Citations (Scopus)

Abstract

A single high dose of interferon-beta (IFNbeta) 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 IFNbeta-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 IFNbeta, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase in other IFNbeta-induced proteins, and to constitutive resistance to DNA damage.
Original languageEnglish
Pages (from-to)2751 - 2763
Number of pages13
JournalEMBO Journal
Volume32
Issue number20
DOIs
Publication statusPublished - 2013

Cite this

Cheon, HyeonJoo ; Holvey-Bates, Elise ; Schoggins, John W ; Forster, Samuel ; Hertzog, Paul John ; Imanaka, Naoko ; Rice, Charles M ; Jackson, Mark W ; Junk, Damian J ; Stark, George. / IFNbeta-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.
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abstract = "A single high dose of interferon-beta (IFNbeta) 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 IFNbeta-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 IFNbeta, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase in other IFNbeta-induced proteins, and to constitutive resistance to DNA damage.",
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Cheon, H, Holvey-Bates, E, Schoggins, JW, Forster, S, Hertzog, PJ, Imanaka, N, Rice, CM, Jackson, MW, Junk, DJ & Stark, G 2013, 'IFNbeta-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

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

In: EMBO Journal, Vol. 32, No. 20, 2013, p. 2751 - 2763.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Holvey-Bates, Elise

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AU - Forster, Samuel

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