Abstract
Evidence is accumulating for the existence of a signal transducer and activator of transcription 2 (STAT2)/interferon regulatory factor 9 (IRF9)-dependent, STAT1-independent interferon alpha (IFNα) signalling pathway. However, no detailed insight exists into the genome-wide transcriptional regulation and the biological implications of STAT2/IRF9-dependent IFNα signalling as compared with interferon-stimulated gene factor 3 (ISGF3). In STAT1-defeicient U3C cells stably overexpressing human STAT2 (hST2-U3C) and STAT1-deficient murine embryonic fibroblast cells stably overexpressing mouse STAT2 (mST2-MS1KO) we observed that the IFNα-induced expression of 2′-5′-oligoadenylate synthase 2 (OAS2) and interferon-induced protein with tetratricopeptide repeats 1 (Ifit1) correlated with the kinetics of STAT2 phosphorylation, and the presence of a STAT2/IRF9 complex requiring STAT2 phosphorylation and the STAT2 transactivation domain. Subsequent microarray analysis of IFNα-treated wild-type (WT) and STAT1 KO cells overexpressing STAT2 extended our observations and identified ∼120 known antiviral ISRE-containing interferon-stimulated genes (ISGs) commonly up-regulated by STAT2/IRF9 and ISGF3. The STAT2/IRF9-directed expression profile of these IFN-stimulated genes (ISGs) was prolonged as compared with the early and transient response mediated by ISGF3. In addition, we identified a group of ‘STAT2/IRF9-specific’ ISGs, whose response to IFNα was ISGF3-independent. Finally, STAT2/IRF9 was able to trigger an antiviral response upon encephalomyocarditis virus (EMCV) and vesicular stomatitis Indiana virus (VSV). Our results further prove that IFNα-activated STAT2/IRF9 induces a prolonged ISGF3-like transcriptome and generates an antiviral response in the absence of STAT1. Moreover, the existence of ‘STAT2/IRF9-specific’ target genes predicts a novel role of STAT2 in IFNα signalling.
Highlights
Interferons (IFNs) are a subset of cytokines that mediate cellular homoeostatic responses to virus infection
No detailed insight exists into the genome-wide transcriptional regulation and the biological implications of signal transducer and activator of transcription 2 (STAT2)/interferon regulatory factor 9 (IRF9)-dependent IFNα signalling as compared with interferon-stimulated gene factor 3 (ISGF3)
We showed that STAT2 homodimers interact with IRF9 (STAT2/IRF9) to activate transcription of interferon-stimulated response element (ISRE) containing IFN-stimulated gene (ISG) in response to IFNα [7]
Summary
Interferons (IFNs) are a subset of cytokines that mediate cellular homoeostatic responses to virus infection. To characterize IFNα-mediated transcriptional responses and identify the genes being regulated by STAT2/IRF9 in relation to ISGF3, we performed microarray experiments comparing human and mouse STAT1 KO cells overexpressing STAT2 with their WT counterparts treated with IFNα for 4 h, 8 h and 24 h.
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