Physical and functional interaction between GATA-3 and Smad3 allows TGF-β regulation of GATA target genes

Background: Members of the GATA family of zinc finger transcription factors are genetically controlled "master" regulators of development in the hematopoietic and nervous systems. Whether GATA factors also serve to integrate epigenetic signals on target promoters is, however, unknown. The transforming growth factor-beta (TGF-beta) superfamily is a large group of phylogenetically conserved secreted factors controlling cell proliferation, differentiation, migration, and survival in multiple tissues.Results: GATA-3, a key regulator of T helper cell development, was found to directly interact with Smad3, an intracellular signal transducer of TGF-beta. Complex formation required a central region in GATA-3 and the N-terminal domain of Smad3. GATA-3 mediated recruitment of Smad3 to GATA binding sites independently of Smad3 binding to DNA, and the two factors cooperated synergistically to regulate transcription from the IL-5 promoter in a TGF-beta-dependent manner. Treatment of T helper cells with TGF-beta promoted the formation of an endogenous Smad3/GATA-3 nuclear complex and stimulated production of the Th2 cytokine IL-10 in a Smad3- and GATA-3-dependent manner.Conclusions: Although Smad proteins are known to interact with a number of general transcription factors, these are insufficient to explain the tissue-specific biology of TGF-beta proteins. Through its interaction with Smad3, GATA-3 is able to integrate a genetic program of cell differentiation with an extracellular signal, providing a molecular framework for the effects of TGF-beta on the development and function of specific subsets of immune cells and possibly other cell types.

背景：锌指转录因子GATA家族成员是造血系统和神经系统发育的受基因控制的“主要”调节因子。然而，GATA因子是否也用于整合靶启动子上的表观遗传信号尚不清楚。转化生长因子 - β（TGF - β）超家族是一大类在系统发育上保守的分泌因子，可控制多种组织中的细胞增殖、分化、迁移和存活。 结果：发现T辅助细胞发育的关键调节因子GATA - 3与TGF - β的细胞内信号转导分子Smad3直接相互作用。复合物的形成需要GATA - 3的一个中心区域和Smad3的N末端结构域。GATA - 3介导Smad3募集到GATA结合位点，而不依赖于Smad3与DNA的结合，并且这两个因子以协同方式合作，以TGF - β依赖的方式调节白细胞介素 - 5启动子的转录。用TGF - β处理T辅助细胞促进了内源性Smad3 / GATA - 3核复合物的形成，并以Smad3和GATA - 3依赖的方式刺激了Th2细胞因子白细胞介素 - 10的产生。 结论：尽管已知Smad蛋白与许多通用转录因子相互作用，但这些不足以解释TGF - β蛋白的组织特异性生物学。通过与Smad3的相互作用，GATA - 3能够将细胞分化的遗传程序与细胞外信号整合，为TGF - β对免疫细胞特定亚群以及可能其他细胞类型的发育和功能的影响提供了一个分子框架。