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

Blaszczyk K, Olejnik A, Nowicka H, Ozgyin L, Chen YL, Chmielewski S, Kostyrko K, Wesoly J, Balint BL, Lee CK, Bluyssen HA

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 hST2-U3C and mST2-MS1KO cells we observed that the IFNα-induced expression of OAS2 and 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. 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 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.

Chromatin Shearing

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January, 2015



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