STAT2/IRF9 directs a prolonged ISGF3-like transcriptional response and antiviral activity in the absence of STAT1

被引：79

作者：

Blaszczyk, Katarzyna ^{[1
]}

Olejnik, Adam ^{[1
]}

Nowicka, Hanna ^{[1
]}

Ozgyin, Lilla ^{[2
]}

Chen, Yi-Ling ^{[3
]}

Chmielewski, Stefan ^{[1
]}

Kostyrko, Kaja ^{[1
]}

Wesoly, Joanna ^{[4
]}

Balint, Balint Laszlo ^{[2
]}

Lee, Chien-Kuo ^{[3
]}

Bluyssen, Hans A. R. ^{[1
]}

机构：

[1] Adam Mickiewicz Univ, Fac Biol, Inst Mol Biol & Biotechnol, Dept Human Mol Genet, Poznan, Poland

[2] Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, Ctr Clin Genom & Personalized Med, H-4012 Debrecen, Hungary

[3] Natl Taiwan Univ, Coll Med, Grad Inst Immunol, Taipei 10764, Taiwan

[4] Adam Mickiewicz Univ, Fac Biol, Inst Mol Biol & Biotechnol, Lab High Throughput Technol, Poznan, Poland

来源：

BIOCHEMICAL JOURNAL | 2015年 / 466卷

关键词：

alternative interferon response pathway; cytokines/interferon; host-pathogen interactions; microarray; STAT transcription factor; signal transduction; GENE-EXPRESSION; GAMMA-INTERFERON; IMMUNE-RESPONSE; IFN-GAMMA; ALPHA; DNA; ACTIVATION; CELLS; INFECTION; CYTOKINES;

D O I：

10.1042/BJ20140644

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (IFN alpha) signalling pathway. However, no detailed insight exists into the genome-wide transcriptional regulation and the biological implications of STAT2/IRF9-dependent IFN alpha 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 IFN alpha-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 IFN alpha-treated wild-type (WT) and STAT1 KO cells overexpressing STAT2 extended our observations and identified similar to 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 IFN alpha 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 IFN alpha-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 IFN alpha signalling.

引用

页码：511 / 524

页数：14

共 43 条

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