title: Interferon Regulatory Factor 8 (IRF8) Impairs Induction of Interferon Induced with Tetratricopeptide Repeat Motif (IFIT) Gene Family Members.
abstract: The chromosomally clustered interferon-induced with tetratricopeptide repeat motif (IFIT) gene family members share structural features at the gene and protein levels. Despite these similarities, different IFIT genes have distinct inducer- and cell type-specific induction patterns. Here, we investigated the mechanism for the observed differential induction of the mouse Ifit1, Ifit2, and Ifit3 genes in B cells and demonstrated that the repressive effect of the transcription factor interferon regulatory factor 8 (IRF8), which is highly expressed in B cells, played an essential role in this regulation. Although IRF8 could impair induction of all three IFIT genes following stimulation of retinoic acid-inducible gene I (RIG-I), it could selectively impair the induction of the Ifit1 gene following IFN stimulation. The above properties could be imparted to IRF8-non-expressing cells by ectopic expression of the protein. Induction of reporter genes, driven by truncated Ifit1 promoters, identified the regions that mediate the repression, and a chromatin immunoprecipitation assay revealed that more IRF8 bound to the IFN-stimulated response element of the Ifit1 gene than to those of the Ifit2 and the Ifit3 genes. Mutational analyses of IRF8 showed that its ability to bind DNA, interact with other proteins, and undergo sumoylation were all necessary to selectively repress Ifit1 gene induction in response to IFN. Our study revealed a new role for IRFs in differentially regulating the induction patterns of closely related IFN-stimulated genes that are located adjacent to one another in the mouse genome.
authors.affiliation: From the Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, christine.white@hudson.org.au.
authors.forename: Christine L
authors.initials: CL
authors.lastname: White
authors.affiliation: From the Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Kessler
authors.affiliation: From the Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, the Graduate Program in Molecular Virology, Case Western Reserve University, Cleveland, Ohio 44106, and.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Dickerman
authors.affiliation: the Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.affiliation: From the Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, the Graduate Program in Molecular Virology, Case Western Reserve University, Cleveland, Ohio 44106, and seng@ccf.org.
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D005810:Multigene Family; D009154:Mutation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D020218:Response Elements / Q000502:physiology*; D000099185:Interferon Regulatory Factor-8
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D050835:Interferon Regulatory Factors; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D000099185:Interferon Regulatory Factor-8; C092573:Ifit1 protein, mouse; C092572:Ifit2 protein, mouse; C087697:Ifit3 protein, mouse
keywords: gene regulation; interferon; interferon regulatory factor (IRF); promoter; transcription regulation