Active repression of IFN regulatory factor-1-mediated transactivation by IFN regulatory factor-4.
IFN regulatory factor-4 (IRF-4) is a transcription factor that is involved in the development and the functions of lymphocytes, macrophages and dendritic cells. Despite their critical roles in immune system regulation, the target genes controlled by IRF-4 are poorly understood. In this study, we determined the consensus DNA-binding sequences preferred for IRF-4 by in vitro binding site selections. IRF-4 preferentially bound to the sequences containing tandem repeats of 5'-GAAA-3', flanked by CpC, in most cases. IRF-4 repressed the promoter bearing tandem copies of the selected binding sequence, while IRF-1 activated the same constructs. Interestingly, the IRF-1-dependent transactivation is inhibited in the presence of IRF-4, but not IRF-2. A series of deletion mutants of IRF-4 revealed that its DNA-binding domain was necessary and sufficient to antagonize the IRF-1-dependent transactivation. This dominant negative action of IRF-4 over IRF-1 was also observed in a natural promoter context, such as the TRAIL gene. These results indicate that IRF-4 acts as a natural antagonist against IRF-1 in immune cells.
Yoshida
Kayo
K
Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Yamamoto
Kazuo
K
Kohno
Tomoko
T
Hironaka
Noriko
N
Yasui
Kiyoshi
K
Kojima
Chojiro
C
Mukae
Hiroshi
H
Kadota
Jun-ichi
J
Suzuki
Shoichi
S
Honma
Kiri
K
Kohno
Shigeru
S
Matsuyama
Toshifumi
T
D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D050436:Regulatory Elements, Transcriptional / Q000235:genetics / Q000276:immunology*; D017384:Sequence Deletion / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D000099218:Interferon Regulatory Factor-4
D051017:Apoptosis Regulatory Proteins; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D000099218:Interferon Regulatory Factor-4; C494257:IRF1 protein, human; C505653:TNFSF10 protein, human