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

• Published in: The EMBO journal Vol. 32; no. 20; pp. 2751 - 2763
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 16.10.2013; Nature Publishing Group
• Subjects: Animals; anti-viral genes; Antiviral Agents - pharmacology; Cells, Cultured; Cercopithecus aethiops; Disease Resistance - drug effects; Disease Resistance - genetics; DNA Damage - drug effects; DNA Damage - genetics; DNA damage resistance; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Humans; Interferon-beta - pharmacology; Interferon-Stimulated Gene Factor 3, gamma Subunit - genetics; Interferon-Stimulated Gene Factor 3, gamma Subunit - metabolism; interferon-β; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; STAT2 Transcription Factor - genetics; STAT2 Transcription Factor - metabolism; Tumor Escape - drug effects; Tumor Escape - genetics; unphosphorylated interferon-stimulated gene factor 3 (U-ISGF3); Vero Cells; Virus Diseases - genetics; Virus Diseases - immunology; Virus Diseases - prevention & control; Viruses - drug effects; Viruses - immunology; Viruses - pathogenicity
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2013.203

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. IFNβ induces the formation of a novel transcriptional complex, U‐ISGF3, which contains un‐phosphorylated STATs. U‐ISGF3 regulates the expression of a subset of IFNβ‐stimulated genes to promote resistance to virus infection and DNA damage.