Yang Shen-Hsi, Sharrocks Andrew D
Faculty of Life Sciences, University of Manchester, Manchester, UK.
EMBO J. 2005 Jun 15;24(12):2161-71. doi: 10.1038/sj.emboj.7600690. Epub 2005 May 26.
The ETS-domain transcription factor Elk-1 is a MAP kinase-inducible transcriptional activator protein. However, in the basal state, its activity is repressed by SUMO-dependent histone deacetylase (HDAC) recruitment. Relief of this repression accompanies the activation process. Here, we demonstrate that PIASx(alpha) acts to facilitate this derepression process. Members of the PIAS family of proteins can act as E3 enzymes that enhance the sumoylation status of a variety of substrates. However, PIASx-mediated coactivation of Elk-1 occurs in an E3 activity-independent manner. PIASx(alpha) binds to Elk-1 in vivo and enhances its transcriptional activity. The coactivating properties of PIASx(alpha) require Elk-1 to be modified with SUMO and the integrity of the SUMO binding motif in PIASx(alpha). PIASx(alpha) activates Elk-1 through alterations in the HAT/HDAC activities associated with Elk-1. In particular, PIASx(alpha) facilitates the loss of the repressive HDAC-2 from sumoylated Elk-1, a key event in the activation of Elk-1 in response to signalling through the ERK MAP kinase pathway. Our data therefore reveal a novel coactivator function for PIASx(alpha) through reversing SUMO-mediated repression of transcription factor activity.
ETS 结构域转录因子 Elk-1 是一种丝裂原活化蛋白激酶诱导的转录激活蛋白。然而，在基础状态下，其活性受到 SUMO 依赖性组蛋白去乙酰化酶（HDAC）募集的抑制。这种抑制的解除伴随着激活过程。在此，我们证明 PIASx（α）有助于促进这种去抑制过程。PIAS 蛋白家族成员可作为 E3 酶，增强多种底物的 SUMO 化状态。然而，PIASx 介导的 Elk-1 共激活以不依赖 E3 活性的方式发生。PIASx（α）在体内与 Elk-1 结合并增强其转录活性。PIASx（α）的共激活特性要求 Elk-1 被 SUMO 修饰且 PIASx（α）中 SUMO 结合基序完整。PIASx（α）通过改变与 Elk-1 相关的组蛋白乙酰转移酶/组蛋白去乙酰化酶（HAT/HDAC）活性来激活 Elk-1。特别是，PIASx（α）促进 SUMO 化的 Elk-1 上抑制性 HDAC-2 的丢失，这是 Elk-1 响应 ERK 丝裂原活化蛋白激酶途径信号转导而激活的关键事件。因此，我们的数据揭示了 PIASx（α）通过逆转 SUMO 介导的转录因子活性抑制作用而具有的一种新型共激活功能。
