Regulation of Type I Interferon Gene Expression by Interferon Regulatory Factor-3

Abstract

Viral infection leads to the transient expression of early inflammatory genes. The proteins encoded by these genes enhance recognition of the infected cells by the host immune system. A group of proteins, called interferons (IFNs), 1 can directly inhibit viral replication. Type I IFNs are encoded by a family of closely related ␣ genes and a single IFNB gene, which are all localized on chromosome 9 (1, 2). The sequences that regulate inducible transcription of these genes are localized within the 100-nucleotide 5Ј-end of the transcriptional start of IFNA and IFNB genes (3, 4). These regions contain a number of a short overlapping GAAAGT-rich sequences that serve as a binding sites for multiple transcriptional factors. Several elements that function as positive regulatory domains (PRD) in virus-infected cells were identified in the promoter region of the IFNB gene (5). It was further shown that the region designated as PRDII contains an NF-kB binding site (6 -8) to which the NF-kB heterodimers induced upon viral infection bind as well as the HMG protein (9). The PRDIV domain was shown to bind the ATF-2 factor and octamer binding protein (10), and the PRDI and PRDIII regions serve as high affinity sites for the binding of the interferon regulatory factors (IRF-1 and IRF-2) (6, 11, 12). The transcriptional activation of this promoter, in virus-infected cells, is a result of the interaction among these multiple transcriptional factors (13) where the virus-induced binding of p50⅐p65 heterodimer plays a crucial role (14,15). In contrast, the IFNA gene promoter region does not contain an NF-B binding site. However, both the murine and human IFNA virus-inducible regions (VRE) contain multiple repeats to the GAAAGT and AAGTGA elements that could serve as binding sites for the IRF-1 and IRF-2 factors (16 -18). In addition, the deletion and mutation analysis of the murine IFNA4 promoter region identified an essential element, named ␣F1 (19), which serves as a recognition site for DNA binding proteins p68 and p96 (20). In the human IFNA1 promoter region, another essential binding site interacting with the TG protein was identified (21). Recent studies have identified a distinct multisubunit complex in virus-induced cells (22).The presence of IRF-like binding sites in the promoter region of the IFNA and IFNB genes indicated that the IRF factors recognizing these sites play an essential role in the induction of IFN genes. The original results of Harada et al. (11) suggested that the up-regulation of these genes is mediated by IRF-1, while the closely related IRF-2 suppresses the expression of these genes. However, the essential role of IRF-1 and IRF-2 in the regulation of IFNA and IFNB gene expression in infected cells was disputed by the finding that mice containing the homozygous deletion of IRF-1 or IRF-2, or fibroblast derived from these mice, were able to induce IFNA and IFNB gene expression upon infection with Newcastle Disease virus (NDV) to the same level as the wild-type mice or cells (23, 24). IRF-1 was shown to pla...

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