Virus-induced Heterodimer Formation betweenIRF-5 and IRF-7 Modulates Assembly of theIFNA Enhanceosome in Vivo and Transcriptional Activity of IFNA Genes

Abstract

Type I interferons (IFN)1 play an essential role in the innate immune response against virus infection (1). In uninfected cells, the expression of IFN genes is tightly regulated. Virus infection activates transcription of type I IFN genes, and the cis-acting virus-responsive elements (VRE), located within the 110 nucleotides 5Ј of the transcription initiation site, are sufficient for virus-mediated activation (2, 3). The VRE of IFNA genes contain purine-rich GAAANN motifs that constitute the specific binding sites (IRF-E and PRDI/III) for the proteins of the interferon regulatory factor (IRF) family, whereas the VRE in the promoter of the IFNB gene contain not only PRDI/ PRDIII elements but also an NF-B (PRDII)-binding site (4).Nine cellular IRF and three viral homologues (vIRF) have been identified (4 -9). All of the cellular IRF share a region of homology in the amino terminus encompassing a highly conserved DNA binding domain (DBD) that is characterized by five tryptophan repeats (4). Three of the repeats contact DNA recognizing the GAAA or AANNGAAA sequences (10 -12). KSHV-encoded IRF that contain an imperfect DNA binding domain are not able to bind DNA with the same specificity as cellular IRF.Several of the cellular IRF were implicated in the regulation of type I IFN gene expression in virus-infected cells. IRF-1 was first identified as an activator of the IFNB gene, whereas IRF-2 antagonized the IRF-1-mediated activation and acted as a suppressor (13-15). Whereas the infected embryonic fibroblasts from IRF-1 Ϫ/Ϫ mice expressed normal levels of IFNA and -B (16, 17), it was observed that IRF-1 associates with the VRE of both human IFNA and IFNB promoters in vivo, thus suggesting that IRF-1 may contribute to the transcriptional regulation of the human IFNA genes (18,19). Three members of the IRF family (IRF-3, IRF-5, and IRF-7) were shown to be direct transducers of virus-mediated signaling and to play a crucial role in the expression of type I IFN genes (19 -26). Whereas IRF-3 is constitutively expressed in all cell types (27), constitutive expression of IRF-7 was observed only in lymphoid cells but could be induced by type I IFN in other cell types (20,28). Expression of IRF-5 was detected primarily in B cells and dendritic cells and was further enhanced by type I IFN (5, 9, 21).In the murine system, induction of type I IFN genes in virus-infected primary embryonic fibroblasts was proposed to proceed by two sequential phases. During the initial phase, which does not require protein synthesis, transcription of IFNB and IFNA4 genes was activated. The second phase, during which the rest of the IFNA subtypes were induced, depended on the IFN-mediated induction of IRF-7 expression (23, 29). However, in recently generated mice with a homozygous deletion of the IRF-7 gene, production of IFN␣ in the isolated mouse embryo fibroblasts was completely abolished, whereas the expression of IFN␤ was significantly reduced (30). These results are consistent with the observations in human cells, where expression of IRF-3 co...

17β-Estradiol Suppresses Cytotoxicity and Proliferative Capacity of Murine Splenic NK1.1+ Cells

“…Runx proteins play important roles in NK cell development and functions through control of the expressions of CD122 and IFN-γ (30). IRF-5 can also act as a repressor of IFN-α/β expression through binding to IRF-7, which results in a heterodimer unable to bind DNA (31). IRF-1 is an important transcription factor in IFN-γ-mediated signaling in the development and function of NK cells.…”

Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells

“…Taken together, our results support the emerging consensus (see Introduction) that IRF5 has a critical role in the production of IFNβ, whereas IRF7 is critical for the production of IFNα. In overexpression experiments IRF5 and IRF7 form heterodimers and the IRF5/ IRF7 heterodimer is reported to be less active than the IRF7 homodimer in stimulating IFNα gene transcription (19). This could explain why the knockdown of IRF5 enhances the CL097-stimulated production of IFNα1 mRNA.…”

The Interferon Regulatory Factor, IRF5, Is a Central Mediator of Toll-like Receptor 7 Signaling

“…Although there are several possibilities to explain this observation, we propose that IRF7 mediates this residual IFN response, since IRF7 is also activated in the TLR7 and TLR8 pathway in a similar manner as IRF5 (17,66). IRF5 has previously been shown to form both homodimers as well as heterodimers with IRF3 or IRF7 in response to virus infection (67). Under these conditions, the formation of IRF5/IRF7 heterodimers can modulate the assembly of the IFNA enhanceosome and alter the profile of IFNA subtypes induced.…”