IFNɑ engages a sustained antiviral response depending on STAT2/IRF9 but not ISGF3 — ASN Events
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  2. Concurrent Symposia 7 Genomic regulation of cytokine and interferon responses
  3. IFNɑ engages a sustained antiviral response depending on STAT2/IRF9 but not ISGF3

IFNɑ engages a sustained antiviral response depending on STAT2/IRF9 but not ISGF3 (#223)

Kasia Blaszczyk 1 , Adam Olejnik 1 , Yi Ling Chen 2 , Stefan Chmielewski 1 , Kaja Kostyrko 1 , Hanna Nowicka 1 , Joanna Wesoly 1 , Chien-Kuo Lee 2 , Hans Bluijssen 1
  1. Department of Human Molecular Genetics, A. Mickiewicz University, Poznan, Poland
  2. Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

Evidence is accumulating for the existence of a STAT2/IRF9-dependent, STAT1-independent IFNα signaling pathway. However, no detailed insight exists in the genome-wide transcriptional regulation and the biological implications of STAT2/IRF9 dependent IFNα signaling as compared to ISGF3. In STAT1 KO cells overexpressing STAT2 we observed that the IFNα-induced expression of classical interferon stimulated genes (ISGs) such as human OAS2 and mouse 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 WT and STAT1 KO cells over-expressing STAT2 extended our observations and identified around 120 known antiviral ISRE-containing ISGs commonly up-regulated by STAT2/IRF9 and ISGF3. The STAT2/IRF9 directed expression profile of these ISGs was prolonged as compared to the early and transient response mediated by ISGF3. ChIP-seq analysis confirmed binding of STAT2 to the promoter of a selection of commonly up-regulated ISGs, in an IFNα-dependent manner in the absence of STAT1.

 In addition, we identified a group of “STAT2/IRF9-specific” ISGs, whose response to IFNα was ISGF3-independent. Finally, STAT2/IRF9 was able to generate a sustained antiviral response upon EMCV and 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 signaling.

Possibly, in cells with prolonged STAT2 phosphorylation kinetics this could provide a level of redundancy to ensure effective induction of an antiviral state and be beneficial for example against viruses that directly block STAT1 and impair the formation of ISGF3.

Preliminary results imply that this situation is very likely to be cell-type specific, where both complexes seem to be involved in different stages of the antiviral response; ISGF3 stimulating a rapid and transient antiviral response whereas STAT2/IRF9 being responsible for a more prolonged antiviral response.