The Role of Acetylation in the Suppressive Effect of STAT3 on Type I Interferon Response
Date Issued
2014
Date
2014
Author(s)
Hsieh, Yu-Hsuan
Abstract
Type I interferons (IFN-I) activate STAT1, STAT2 and STAT3. While STAT1 and STAT2 play positive roles in IFN-I-mediated antiviral responses, STAT3 negatively regulates the responses. Interestingly, N-terminal domain (NTD) of STAT3 is sufficient to suppress IFN-I-induced downstream gene expression. Nevertheless, the detailed mechanisms remain unclear. STAT3 NTD did not affect IFN-I-induced phosphorylation and nuclear translocation of STAT1. Instead, STAT3 affects the binding of ISGF3 to the promoters of ISGs. However, STAT3 NTD interacts with STAT1 and STAT3 can be acetylated at its N-terminal domain. First of all, we investigated the effect of STAT3 acetylation in the NTD. STAT3K49R/K87R mutant blocked the suppressive effect of STAT3 on IFN-I-induced gene expression, suggesting that acetylation at STAT3 NTD may be involved in the negative regulation of IFN response. We further investigated the role of acetylation in detailed mechanism using pharmacological inhibitors and RNA silencing for histone deacetylase (HDACs). The susceptibility to Trichostatin A (TSA)-mediated suppression of IFN-dependent ISG induction was different in WT and STAT3KO MEFs. However, the treatment of nicotinamide did not have any effect, suggesting that STAT3 may be involved in the regulation of IFN-I response by class I and II but not class III HDACs. Double knockdown of HDAC1 and HDAC2 in either Stat3f/f or Ad-Cre Stat3-/- MEFs suppressed ISG expression in response to IFN-I. However, the suppressive effect was much prominent in STAT3-deficient MEFs than in control MEFs. We hypothesized that STAT3 may inhibit the interaction between HDAC and STAT1, therefore, increasing the impact of HDAC on STAT1 in the absence of STAT3. Indeed, increased interaction between STAT1 and HDAC1 was observed in 293T cells that had been treated with shSTAT3. In sum, these results suggest that STAT3 may negatively regulate IFN-I response through acetylation-dependent mechanism involves HDACs, including HDAC1 and maybe HDAC2.
Subjects
第一型干擾素
訊息傳導與轉錄子三
抗病毒反應
乙醯化
組織蛋白去乙醯酶
Type
thesis
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