The suppressive effect of STAT3 on type I interferon-mediated response
Date Issued
2012
Date
2012
Author(s)
Cheng, Tzu-Pei
Abstract
Type I IFNs, activating STAT1, STAT2, and STAT3, are crucial for antiviral response. Stimulation of type I IFN induces the production of antiviral proteins in a STAT1- and STAT2-dependent manner. However, the function of STAT3 in type I IFN response was not completely understood. Recently, STAT3 was reported to negatively regulate type I IFN-mediated antiviral response. Cells lacking STAT3 displayed enhanced ISGs expression and antiviral activity upon IFN stimulation. However, the detailed mechanism remains elusive. To investigate the underlying mechanism, we used STAT1 and STAT3 double knockout (DKO) MEFs that had been restored with STAT1, STAT3, or both molecules. STAT1 or STAT3 was expressed in the DKO MEFs at a level comparable to WT MEFs. Using expression microarray and RT-QPCR, we also found that in STAT1/STAT3-restored MEFs, STAT3 could negatively regulate STAT1-dependent type I IFN-mediated gene induction and antiviral response as compared with STAT1-restored MEFs. Furthermore, using ChIP assay we showed that STAT3 impeded the recruitment of ISGF3 complex to ISRE of MDA5 and IFIT1, two IFN-stimulated genes (ISGs), following type I IFN stimulation. Since NH2-terminal domain (amino acids 1 to 134) of STAT3 was able to confer suppressive effect, we further dissect the involvement of two potential acetylation sites 49K and 87K in suppressive activating ofSTAT3. Single or double K to R mutations of these two sites in STAT3 blocked its transactivation ability. However, only K49R or RR mutants inhibited the suppressive effect of STAT3 on type I IFN response. Interestingly, IFNα-dependent acetylation of STAT3 was abolished in RR mutant STAT3. Together, these results indicate that STAT3 may affect type I IFN response by blocking the recruitment of ISGF3 complex to the promoter of ISGs. Acetylation of K49 and K87 in NTD of STAT3 may be involved in the negative regulator of the IFN response.
Subjects
STAT3
IFN
microarray
Type
thesis
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