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

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

doi:10.1038/emboj.2013.203

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.

Highlights

Type I interferons (IFNs a and b) drive the expression of genes that encode proteins with anti-viral, anti-proliferative, proapoptotic, and pro-inflammatory functions
The expression of anti-viral genes is sustained for several days after IFN b treatment, along with increased levels of STAT1, STAT2, and IFN response factor 9 (IRF9) proteins Over a hundred genes are induced by IFNb quickly, in response to the tyrosine phosphorylation of signal transducers and activators of transcription (STATs) 1 and 2
In contrast to the sustained expression of the four anti-viral genes noted above, the expression of IRF1, an ISG whose expression is driven by IFN-stimulated gene factor 3 (ISGF3) and not by U-STAT1, increased transiently and decreased in parallel with the levels of phosphorylated STATs 1 and 2 (Figure 1B), showing that, even if phosphorylated ISGF3 was still present at levels below our ability to detect it, there was not enough to drive the expression of this target gene

Summary

Introduction

Type I interferons (IFNs a and b) drive the expression of genes that encode proteins with anti-viral, anti-proliferative, proapoptotic, and pro-inflammatory functions. Sustained expression of many of the initially induced proteins is deleterious to cell survival (Borden et al, 2007), we have discovered that the increased expression of the proteins encoded by a subset of these genes is sustained for many days (Cheon and Stark, 2009). They provide a selective advantage and cells can tolerate them. We show that prolonged exposure of cells to a low level of IFNb induces a steady state in which only the U-ISGF3-dependent genes are expressed, suggesting that secretion of IFNb by cancer cells may account for their similar phenotype

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Conclusion