Pai Sung-Yun, Kang Bok Yun, Sabadini Amelia M, Parisini Emilio, Truitt Morgan L, Ho I-Cheng
Division of Pediatric Hematology-Oncology, Children's Hospital, Department of Pediatric Oncology, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2008 Jan 15;180(2):1050-9. doi: 10.4049/jimmunol.180.2.1050.
GATA-3, the only T cell-specific member of the GATA family of transcription factors, is essential for the intrathymic development of CD4+ T cells and for the differentiation of Th2 cells. However, whether distinct biochemical features, unique to GATA-3 compared with other GATA family members, are required to drive T cell transcriptional programs or whether the T cell-specific functions of GATA-3 can simply be ascribed to its expression pattern is unclear. Nor do we understand the protein structural requirements for each individual function of GATA-3. In this study, we report that a heterologous GATA factor, GATA-4, was competent in supporting the development of CD4+ T cells but could not fully compensate for GATA-3 in regulating the expression of Th cytokines. Specifically, GATA-3 was more potent than GATA-4 in driving the production of IL-13 due to a mechanism independent of DNA binding or chromatin remodeling of the IL-13 locus. The difference was mapped to a partially conserved region C-terminal to the second zinc finger. Converting a single proline residue located in this region of GATA-4 to its counterpart, a methionine of GATA-3, was sufficient to enhance the IL-13-promoting function of GATA-4 but had no effect on other cytokines. Taken together, our data demonstrate that the unique function of GATA-3 is conferred by both its cell type-specific expression and distinct protein structure.
GATA-3是转录因子GATA家族中唯一的T细胞特异性成员，对CD4+T细胞的胸腺内发育以及Th2细胞的分化至关重要。然而，与其他GATA家族成员相比，GATA-3独特的生化特性是否是驱动T细胞转录程序所必需的，或者GATA-3的T细胞特异性功能是否仅仅归因于其表达模式，目前尚不清楚。我们也不了解GATA-3各个功能的蛋白质结构要求。在本研究中，我们报告了一种异源GATA因子GATA-4能够支持CD4+T细胞的发育，但在调节Th细胞因子表达方面不能完全补偿GATA-3。具体而言，由于一种独立于IL-13基因座DNA结合或染色质重塑的机制，GATA-3在驱动IL-13产生方面比GATA-4更有效。这种差异定位于第二个锌指C末端的一个部分保守区域。将位于GATA-4该区域的单个脯氨酸残基转换为其对应物，即GATA-3的甲硫氨酸，足以增强GATA-4促进IL-13的功能，但对其他细胞因子没有影响。综上所述，我们的数据表明，GATA-3的独特功能是由其细胞类型特异性表达和独特的蛋白质结构共同赋予的。
