title: Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter.
abstract: 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.
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Hsiao-Wei
authors.initials: HW
authors.lastname: Tsao
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Tai
authors.forename: William
authors.initials: W
authors.lastname: Tseng
authors.forename: Hui-Hsin
authors.initials: HH
authors.lastname: Chang
authors.forename: Roland
authors.initials: R
authors.lastname: Grenningloh
authors.forename: Shi-Chuen
authors.initials: SC
authors.lastname: Miaw
authors.forename: I-Cheng
authors.initials: IC
authors.lastname: Ho
mesh_terms: D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport; D050784:Proto-Oncogene Protein c-ets-1 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D018417:Th1 Cells / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism
chemical_list: C494041:ETS1 protein, human; C494042:Ets1 protein, mouse; D007376:Interleukin-2; D046912:Multiprotein Complexes; D050778:NFATC Transcription Factors; C513258:Prdm1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D002118:Calcium
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