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

140 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
JournalThe EMBO Journal
Volume32
Issue number20
DOIs
Publication statusPublished - 2013

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