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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Interaction of GATA-3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes
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Interaction of GATA-3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes

机译：GATA-3 / T-bet转录因子的相互作用调节Th1 / Th2淋巴细胞上唾液酸化的Lewis X归巢受体的表达

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摘要

Selectin-dependent cell adhesion mediates inflammatory extravasation and routine homing of lymphocytes. Most resting peripheral T lymphocytes lack expression of sialyl Lewis X, the carbohydrate ligand for selectins, and are induced to strongly express it upon activation. T helper 1 (Th1) cells are known to more preferentially express sialyl Lewis X as compared with T helper 2 (Th2) cells upon activation. The molecular basis for this preferential expression, however, has not been elucidated to date. Here we show that the gene for fucosyltransferase VII (FUT7), the rate-limiting enzyme for sialyl Lewis X synthesis, is a unique example of the human genes with binding sites for both GATA-3 and T-bet, two opposing factors for Th1 and Th2 development, and is regulated transcriptionally by a balance of the two interacting transcription factors. T-bet promotes and GATA-3 represses FUT7 transcription. bur results indicated that T-bet interferes with the binding of GATA-3 to its target DNA, and also that GATA-3 significantly interferes with the binding of T-bet to the FUT7 promoter. T-bet has a binding ability to GATA-3, CBP/P300, and Sp1 to form a transcription factor complex, and GATA-3 regulates FUT7 transcription by phosphorylation-dependently recruiting histone deacetylase (HDAC)-3/HDAC-5 and by competing with CBP/P300 in binding to the N terminus of T-bet. Suppression of GATA-3 activity by dominant-negative GATA-3 or repressor of GATA (ROG) was necessary to attain a maximum expression of FUT7 and sialyl Lewis X in human T lymphoid cells. These results indicate that the GATA-3/T-bet transcription factor complex regulates the cell-lineage-specific expression of the lymphocyte homing receptors.
机译：选择素依赖性细胞粘附介导炎症外渗和淋巴细胞的常规归巢。大多数静止的外周T淋巴细胞缺乏唾液酸路易斯X的表达，唾液酸的路易斯X是选择素的碳水化合物配体，并被诱导在激活时强烈表达。与激活后的T辅助2（Th2）细胞相比，已知T辅助1（Th1）细胞更优先表达唾液酸化的LewisX。然而，迄今为止尚未阐明该优先表达的分子基础。在这里，我们显示了岩藻糖基转移酶VII（FUT7）的基因，唾液酸路易斯X合成的限速酶，是人类基因的独特实例，该基因具有GATA-3和T-bet（Th1的两个相对因子）的结合位点以及Th2的发育，并受两个相互作用的转录因子平衡的转录调控。 T-bet促进GATA-3抑制FUT7转录。结果表明，T-bet干扰GATA-3与其靶DNA的结合，而且GATA-3显着干扰T-bet与FUT7启动子的结合。 T-bet具有与GATA-3，CBP / P300和Sp1结合的能力，形成转录因子复合物，而GATA-3通过磷酸化依赖性地募集组蛋白脱乙酰基酶（HDAC）-3 / HDAC-5和通过磷酸化来调节FUT7转录。与CBP / P300竞争与T-bet的N末端结合。必须通过显性负性GATA-3或GATA阻遏物（ROG）抑制GATA-3活性，以在人T淋巴样细胞中获得FUT7和唾液酸化Lewis X的最大表达。这些结果表明，GATA-3 / T-bet转录因子复合物调节淋巴细胞归巢受体的细胞谱系特异性表达。

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