ATF6 as a transcription activator of the endoplasmic reticulum stress element: Thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1
ATF6 as a transcription activator of the endoplasmic reticulum stress element: Thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1
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DOI：
10.1128/mcb.20.14.5096-5106.2000
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发表时间：
2000-07-01
影响因子：
5.3
通讯作者：
Lee, AS
中科院分区：
文献类型：
--
作者：
Li, MQ;Baumeister, P;Lee, AS
ATF 6是亮氨酸拉链蛋白家族的一员，通过激活内质网应激元件（ERSE），组成型诱导葡萄糖调节蛋白（grp）基因的启动子。为了理解在经历由毒胡萝卜素（Tg）处理介导的ER钙耗竭应激的细胞中由ATF 6诱导grp 78的机制，我们发现ATF 6本身经历Tg应激诱导的变化。在非应激细胞中，ATF 6主要与核周区相关，它含有一个假定的短跨膜结构域。在Tg应激后，ATF 6蛋白水平最初下降，但很快恢复，并出现更快的迁移形式。这种新的形式的ATF 6回收可溶性核蛋白的生化分级，与增强的核定位的ATF 6所揭示的免疫荧光。最佳的ATF 6刺激需要至少两个拷贝的ERSE和完整的三方结构的ERSE。最重要的是一个功能性的NF-Y复合物和一个高亲和力的NF-Y结合位点，赋予不同的ERSE之间的选择性为ATF 6诱导。此外，我们发现YY 1与ATF 6相互作用，并且在TG处理的细胞中可以增强ATF 6活性。ATF 6的ERSE刺激活性表现出与人Ire 1 p不同的特性，Ire 1 p是哺乳动物未折叠蛋白反应的上游调节因子。ATF 6需要一个高亲和力的NF-Y位点，但不需要人Ire 1 p活性，这表明它们通过不同的途径刺激ERSE。
ATF6, a member of the leucine zipper protein family, can constitutively induce the promoter of glucose-regulated protein (grp) genes through activation of the endoplasmic reticulum (ER) stress element (ERSE). To understand the mechanism of grp78 induction by ATF6 in cells subjected to ER calcium depletion stress mediated by thapsigargin (Tg) treatment, we discovered that ATF6 itself undergoes Tg stress induced changes. In nonstressed cells, ATF6, which contains a putative short transmembrane domain, is primarily associated with the perinuclear region. Upon Tg stress, the ATF6 protein level dropped initially but quickly recovered with the additional appearance of a faster-migrating form. This ne cv form of ATF6 was recovered as soluble nuclear protein by biochemical fractionation, correlating with enhanced nuclear localization of ATF6 as revealed by immunofluorescence. Optimal ATF6 stimulation requires at least two copies of the ERSE and the integrity of the tripartite structure of the ERSE. Of primary importance is a functional NF-Y complex and a high-affinity NF-Y binding site that confers selectivity among different ERSEs for ATF6 inducibility. In addition, we showed that YY1 interacts with ATF6 and in Tg-treated cells can enhance ATF6 activity. The ERSE stimulatory activity of ATF6 exhibits properties distinct from those of human Ire1p, an upstream regulator of the mammalian unfolded protein response. The requirement for a high-affinity NF-Y site for ATF6 but not human Ire1p activity suggests that they stimulate the ERSE through diverse pathways.