Sumoylation-dependent control of homotypic and heterotypic synergy by the kruppel-type zinc finger protein ZBP-89
Sumoylation-dependent control of homotypic and heterotypic synergy by the kruppel-type zinc finger protein ZBP-89
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DOI：
10.1074/jbc.m708130200
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发表时间：
2007-12-14
影响因子：
4.8
通讯作者：
Iniguez-Lluhi, Jorge A.
中科院分区：
文献类型：
--
作者：
Chupreta, Sergey;Brevig, Holly;Iniguez-Lluhi, Jorge A.
Kruppel 样转录因子 ZBP-89 是一种序列特异性调节因子，在细胞生长和分化中发挥关键作用，特别是在内胚层和生殖细胞谱系中。 ZBP-89 与 Sp 样家族的其他成员共享多个基因调控区域中富含 GC 序列的重叠序列特异性。定义控制 ZBP-89 内在功能及其与其他调节剂的竞争性和非竞争性功能相互作用的机制对于理解 ZBP-89 如何发挥其生物学功能至关重要。我们现在描述了多个小泛素样修饰剂 (SUMO) 同工型对 ZBP-89 的翻译后修饰发生在 DNA 结合域两侧的两个保守的协同控制基序处。功能性苏酰化并没有直接改变 ZBP-89 与来自各个位点的其他 Sp 样因子竞争的能力。然而，在带有多个反应元件的启动子上，这种修饰抑制了 ZBP-89 和 Sp1 之间的功能合作。对 ZBP-89 在没有竞争因子的细胞环境中的特性的分析表明，尽管它本身表现为适度的激活剂，但它与糖皮质激素受体等异源激活剂具有有效的协同作用。值得注意的是，我们发现当与 ZBP-89 缀合时，SUMO 通过关键的保守功能表面对这种协同相互作用产生强烈的抑制作用。通过调节高阶功能相互作用，SUMO化提供了一种可逆的翻译后机制来控制 ZBP-89 的活性。
The Kruppel-like transcription factor ZBP-89 is a sswequence-specific regulator that plays key roles in cellular growth and differentiation especially in endodermal and germ cell lineages. ZBP-89 shares with other members of the Sp-like family an overlapping sequence specificity for GC-rich sequences in the regulatory regions of multiple genes. Defining the mechanisms that govern the intrinsic function of ZBP-89 as well as its competitive and non-competitive functional interactions with other regulators is central to understand how ZBP- 89 exerts its biological functions. We now describe that post-translational modification of ZBP-89 by multiple small ubiquitin-like modifier (SUMO) isoforms occurs at two conserved synergy control motifs flanking the DNA binding domain. Functionally sumoylation did not directly alter the ability of ZBP-89 to compete with other Sp-like factors from individual sites. At promoters bearing multiple response elements, however, this modification inhibited the functional cooperation between ZBP-89 and Sp1. Analysis of the properties of ZBP-89 in cellular contexts devoid of competing factors indicated that although on its own it behaves as a modest activator it potently synergizes with heterologous activators such as the glucocorticoid receptor. Notably we found that when conjugated to ZBP-89, SUMO exerts a strong inhibitory effect on such synergistic interactions through a critical conserved functional surface. By regulating higher order functional interactions, sumoylation provides a reversible post-translational mechanism to control the activity of ZBP-89.