TY - JOUR
T1 - Interferon regulatory factor 8 (IRF8) impairs induction of interferon induced with tetratricopeptide repeat motif (IFIT) gene family members
AU - White, Christine L.
AU - Kessler, Patricia M.
AU - Dickerman, Benjamin K.
AU - Ozato, Keiko
AU - Sen, Ganes C.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants CA068782, CA062220, and AI073303 (to G. C. S.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the Lerner Research Institute flow cytometry core for assistance in sorting lentivirally infected cells, the genomics core for assistance in sequencing plasmids, and Debasis Pore and Neetu Gupta for purified B cells. We also thank Dr. Frances Cribbin (Hudson Institute of Medical Research) for editorial assistance with manuscript preparation.
Publisher Copyright:
© 2016, American Society for Biochemistry and Molecular Biology Inc. All rights reserved.
PY - 2016/6
Y1 - 2016/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84976402611&partnerID=8YFLogxK
U2 - 10.1074/jbc.M115.705467
DO - 10.1074/jbc.M115.705467
M3 - Article
C2 - 27137933
AN - SCOPUS:84976402611
SN - 0021-9258
VL - 291
SP - 13535
EP - 13545
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 26
ER -