title: Interferon regulatory factor 2 binding protein 2 is a new NFAT1 partner and represses its transcriptional activity.
abstract: The nuclear factor of activated T cells (NFAT) family of transcription factors is expressed in a wide range of cell types and regulates genes involved in cell cycle, differentiation, and apoptosis. NFAT proteins share two well-conserved regions, the regulatory domain and the DNA binding domain. The N- and C-terminal ends are transactivation sites and show less sequence similarity, whereas their molecular functions remain poorly understood. Here, we identified a transcriptional repressor, interferon regulatory factor 2 binding protein 2 (IRF-2BP2), which specifically interacts with the C-terminal domain of NFAT1 among the NFAT family members. IRF-2BP2 was described as a corepressor by inhibiting both enhancer-activated and basal transcription. Gene reporter assays demonstrated that IRF-2BP2 represses the NFAT1-dependent transactivation of NFAT-responsive promoters. The ectopic expression of IRF-2BP2 in CD4 T cells resulted in decreased interleukin-2 (IL-2) and IL-4 production, supporting a repressive function of IRF-2BP2 for NFAT target genes. Furthermore, NFAT1 and IRF-2BP2 colocalized in the nucleus in activated cells, and the mutation of a newly identified nuclear localization signal in the IRF-2BP2 rendered it cytoplasmic, abolishing its repressive effect on NFAT1 activity. Collectively, our data demonstrate that IRF-2BP2 is a negative regulator of the NFAT1 transcription factor and suggest that NFAT1 repression occurs at the transcriptional level.
authors.affiliation: Division of Cellular Biology, Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Flávia R G
authors.initials: FR
authors.lastname: Carneiro
authors.forename: Renata
authors.initials: R
authors.lastname: Ramalho-Oliveira
authors.forename: Giuliana P
authors.initials: GP
authors.lastname: Mognol
authors.forename: João P B
authors.initials: JP
authors.lastname: Viola
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D050836:Interferon Regulatory Factor-2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016415:Sequence Alignment; D014157:Transcription Factors; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C494229:IRF2 protein, human; C475082:IRF2BP2 protein, human; D050836:Interferon Regulatory Factor-2; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D014157:Transcription Factors