Abstract
Recent studies implicate the interferon regulatory factors (IRF), IRF-3 and IRF-7, as key activators of Type 1 interferon genes, as well as the RANTES (regulated on activation normal T cell expressed) chemokine gene. Both IRF-3 and IRF-7 are regulated in part by virus-induced C-terminal phosphorylation, leading to nuclear translocation, stimulation of DNA binding, and transcriptional activities. Structure-function studies with IRF-7 suggested a complex organization of the C-terminal region, with a constitutive activation domain located between amino acids 150-246, an accessory inducibility region at the very end of IRF-7 between amino acids 467 and 503, and an inhibitory region (amino acids 341-467) adjacent to the C-terminal end that interferes with transactivation. Furthermore, an element that increases basal and virus-inducible activity is located between amino acids 278 and 305. A transcriptionally active form of IRF-7 was also generated by substitution of Ser-477 and Ser-479 residues with the phosphomimetic Asp. IRF-7, particularly IRF-7(S477D/S479D), was a strong transactivator of type I interferon and RANTES chemokine gene expression. Unlike wild type IRF-3, IRF-7 overexpression was able to stimulate inteferon gene expression in the absence of virus infection. Using tagged versions of IRF-7 and IRF-3, the formation of homo- and heterodimers was detected by co-immunoprecipitation. These results demonstrate that IRF-3 and IRF-7 transcription factors possess distinct structural characteristics that impart complementary rather than redundant functional roles in cytokine gene activation.
Highlights
Recent studies implicate the interferon regulatory factors (IRF), IRF-3 and IRF-7, as key activators of Type 1 interferon genes, as well as the RANTES chemokine gene
Structure-function studies with IRF-7 suggested a complex organization of the C-terminal region, with a constitutive activation domain located between amino acids 150 –246, an accessory inducibility region at the very end of IRF-7 between amino acids 467 and 503, and an inhibitory region adjacent to the C-terminal end that interferes with transactivation
Multiple Domain Structure of IRF-7—The IRF-7 transcription factor shares many structural features with the IRF-3 factor, including the N-terminal DNA binding domain common to all IRF members, a putative IRF association domain in the C-terminal half of the protein, and a serine-rich domain located at the C-terminal end of the molecule between aa 471 and 487, which is the target of virus-inducible phosphorylation [26, 27]
Summary
Recent studies implicate the interferon regulatory factors (IRF), IRF-3 and IRF-7, as key activators of Type 1 interferon genes, as well as the RANTES (regulated on activation normal T cell expressed) chemokine gene. Both IRF-3 and IRF-7 are regulated in part by virusinduced C-terminal phosphorylation, leading to nuclear translocation, stimulation of DNA binding, and transcriptional activities. 1 The abbreviations used are: IFN, interferon; JAK-STAT, Janus kinase-signal transducer and activator of transcription; IRF, interferon regulatory factor; IAD, IRF association domain; RANTES, regulated on activation normal T cell expressed; PAGE, polyacrylamide gel electrophoresis; GFP, green fluorescence protein; VAD, virus-activated domain; aa, amino acid(s); CBP, CREB-binding protein; ISRE, interferonstimulated response element. Other studies demonstrated that transcription of the CC-chemokine RANTES was up-regulated by virus infection, mediated through IRF-3 activation and binding to overlapping ISRE-like elements in the Ϫ100 region of the RANTES promoter [23]
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