title: STAT2/IRF9 directs a prolonged ISGF3-like transcriptional response and antiviral activity in the absence of STAT1.
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.
authors.affiliation: *Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Blaszczyk
authors.affiliation: *Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Olejnik
authors.affiliation: *Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Nowicka
authors.affiliation: †University of Debrecen/Medical Faculty, Department of Biochemistry and Molecular Biology Centre for Clinical Genomics and Personalized Medicine, Debrecen, Hungary.
authors.forename: Lilla
authors.initials: L
authors.lastname: Ozgyin
authors.affiliation: ‡Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Chen
authors.affiliation: *Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Chmielewski
authors.affiliation: *Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Kaja
authors.initials: K
authors.lastname: Kostyrko
authors.affiliation: §Laboratory of High Throughput Technologies, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wesoly
authors.affiliation: †University of Debrecen/Medical Faculty, Department of Biochemistry and Molecular Biology Centre for Clinical Genomics and Personalized Medicine, Debrecen, Hungary.
authors.forename: Balint Laszlo
authors.initials: BL
authors.lastname: Balint
authors.affiliation: ‡Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chien-Kuo
authors.initials: CK
authors.lastname: Lee
authors.affiliation: *Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Hans A R
authors.initials: HA
authors.lastname: Bluyssen
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D000998:Antiviral Agents; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; C494228:Isgf3g protein, mouse