Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 39; pp. 15776 - 15781
• Main Authors: Tsao, Hsiao-Wei, Tai, Tzong-Shyuan, Tseng, William, Chang, Hui-Hsin, Grenningloh, Roland, Miaw, Shi-Chuen, Ho, I-Cheng
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.09.2013; National Acad Sciences
• Subjects: Animals; Antibodies; B lymphocytes; Base Sequence; Biological Sciences; Calcium - metabolism; Cell nucleus; Cell Nucleus - metabolism; Cytoplasm; Gene Knockout Techniques; Humans; Interleukin-2 - biosynthesis; Interleukin-2 - genetics; Lymphocytes; Mice; Molecular Sequence Data; Multiprotein Complexes - metabolism; NFATC transcription factors; NFATC Transcription Factors - metabolism; Plasma cells; Positive Regulatory Domain I-Binding Factor 1; Promoter Regions, Genetic; Protein Binding - genetics; Protein Transport; Proteins; Proto-Oncogene Protein c-ets-1 - deficiency; Proto-Oncogene Protein c-ets-1 - metabolism; Ribonucleic acid; RNA; Signal Transduction; T cell receptors; T lymphocytes; Th1 Cells - metabolism; Transcription factors; Transcription Factors - deficiency; Transcription Factors - metabolism; Transcriptional regulatory elements
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1304343110

E26 transformation-specific sequence 1 (Ets-1), the prototype of the ETS family of transcription factors, is critical for the expression of IL-2 by murine Th cells; however, its mechanism of action is still unclear. Here we show that Ets-1 is also essential for optimal production of IL-2 by primary human Th cells. Although Ets-1 negatively regulates the expression of Blimp1, a known suppressor of IL-2 expression, ablation of B lymphocyte-induced maturation protein 1 (Blimp1) does not rescue the expression of IL-2 by Ets-1-deficient Th cells. Instead, Ets-1 physically and functionally interacts with the nuclear factor of activated T-cells (NFAT) and is required for the recruitment of NFAT to the IL-2 promoter. In addition, Ets-1 is located in both the nucleus and cytoplasm of resting Th cells. Nuclear Ets-1 quickly exits the nucleus in response to calcium-dependent signals and competes with NFAT proteins for binding to protein components of noncoding RNA repressor of NFAT complex (NRON), which serves as a cytoplasmic trap for phosphorylated NFAT proteins. This nuclear exit of Ets-1 precedes rapid nuclear entry of NFAT and Ets-1 deficiency results in impaired nuclear entry, but not dephosphorylation, of NFAT proteins. Thus, Ets-1 promotes the expression of IL-2 by modulating the activity of NFAT.