Abstract
Type I interferon (IFN) plays a critical role in the innate immunity against viral infection. Expression of IFNA genes in infected cells is cell type-dependent and is regulated at the transcriptional level. The present study is focused on the molecular mechanism underlying the differential expression of human IFNA1 and A2 genes. Two nucleotides, at positions -98 and -81 of IFNA1 and A2 promoter, were pivotal to the differential expression. The DNA pull-down and chromatin precipitation assays have shown that nuclear interferon regulatory factor (IRF)-3 and IRF-7 as well as IRF-1 bind to IFNA1 virus-responsive element (VRE). Interestingly, overexpression of IRF-7 increased the otherwise weak binding of both IRF-3 and IRF-7 to IFNA2 VRE. These data together with the results of two-step chromatin immunoprecipitation strongly suggest that the IRF-3 and IRF-7 bind to IFNA1 promoter as a dimer. Furthermore, binding of IRF-3 and IRF-7 to IFNA VRE is associated with the presence of acetylated histone H3, suggesting that histone acetyltransferase(s) is tethered together with virus-activated IRF-3 and IRF-7 to the IFNA1 promoter. In addition, the constitutively active IRF-3 (5D) and IRF-7 (2D) mutants activate the endogenous IFNA genes in uninfected cells; however, the expression profile of IFNA is not identical to that induced by viral infection.
Highlights
Type I interferon (IFN)1 plays an essential role in innate immune response against virus infection [1]
The results have indicated a critical role of interferon regulatory factor (IRF)-3/IRF-7 heterodimers in the stimulation of transcription of these two IFNA genes and showed that the relative levels of IRF-7 in the cells affect the assembly of IRF-1, IRF-3, IRF-7, and acetyltransferase on the transcriptionally active promoters of IFNA1 and IFNA2 genes in infected cells
To determine the cis-acting elements that are responsible for the differential expression of IFNA1 and IFNA2 genes in infected cells, we have focused on the Ϫ103 to Ϫ67 region of IFNA1 promoter, which was previously showed by the DNase footprinting analysis, to bind recombinant IRF-3 and IRF-7 [17]
Summary
Type I interferon (IFN) plays an essential role in innate immune response against virus infection [1]. The second phase, during which the rest of IFNA subtypes is induced, depends on IFN-mediated induction of IRF-7 expression [20, 26] Consistent with this observation are the recent results from infected mouse embryonic fibroblasts with homozygous deletion of IRF-3 gene that displayed significant reduction of Type I IFN expression, and an additional defect in IFN signaling pathway completely abolished the virus-mediated induction of Type I IFN genes [21]. Induction of IFNA genes can be rescued in non-IRF-7-expressing cells by overexpression of IRF-5, but activation of this transcription factor is virus-specific and results in expression of different IFNA subtypes than found in infected cells expressing IRF-7 [24]. The interaction between the members of IRF family was found to result in novel biological activities [38]
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