Endoplasmic reticulum stress induction of the Grp78/BiP promoter: Activating mechanisms mediated by YY1 and its interactive chromatin modifiers
Endoplasmic reticulum stress induction of the Grp78/BiP promoter: Activating mechanisms mediated by YY1 and its interactive chromatin modifiers
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DOI：
10.1128/mcb.25.11.4529-4540.2005
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发表时间：
2005-06-01
影响因子：
5.3
通讯作者：
Lee, AS
中科院分区：
文献类型：
--
作者：
Baumeister, P;Luo, SZ;Lee, AS
未折叠的蛋白质反应是一种进化上保守的机制，细胞借此对靶向内质网（ER）的应激条件作出反应。GRP78/BiP（一种促存活ER伴侣）启动子的转录激活已被广泛用作UPR开始的指标。YY1是一种组成型表达的多功能转录因子，仅在ER应激条件下激活Grp78启动子。以前，在体内足迹分析表明，YY1结合位点的ER应激反应元件的Grp78启动子表现出ER应激诱导的变化的占用。为了理解这些独特现象的潜在机制，我们进行了染色质免疫沉淀分析，揭示了YY1在ER应激时仅占据Grp78启动子，并且部分由核形式的ATF 6介导。我们发现YY 1是ATF6的一个重要的辅激活因子，并揭示了它们之间特定的相互作用结构域。使用针对YY1的小干扰RNA和编码ATF6 α的基因的插入突变，我们提供了直接的证据，证明YY1和ATF6是Grp78的最佳应激诱导所必需的。我们还发现，通过YY 1与精氨酸甲基转移酶PRMT 1的相互作用增强了Grp78启动子的ER应激诱导，并通过组蛋白H4上精氨酸3残基的甲基化证明了其作用。此外，我们检测到ER应激诱导的组蛋白乙酰转移酶p300与Grp78启动子和组蛋白H4乙酰化的结合。ER应激介导的转录因子结合和染色质修饰的Grp78启动子，导致其激活的模型提出。
The unfolded protein response is an evolutionarily conserved mechanism whereby cells respond to stress conditions that target the endoplasmic reticulum (ER). The transcriptional activation of the promoter of GRP78/BiP, a prosurvival ER chaperone, has been used extensively as an indicator of the onset of the UPR. YY1, a constitutively expressed multifunctional transcription factor, activates the Grp78 promoter only under ER stress conditions. Previously, in vivo footprinting analysis revealed that the YY1 binding site of the ER stress response element of the Grp78 promoter exhibits ER stress-induced changes in occupancy. Toward understanding the underlying mechanisms of these unique phenomena, we performed chromatin immunoprecipitation analyses, revealing that YY1 only occupies the Grp78 promoter upon ER stress and is mediated in part by the nuclear form of ATF6. We show that YY1 is an essential coactivator of ATF6 and uncover their specific interactive domains. Using small interfering RNA against YY1 and insertional mutation of the gene encoding ATF6 alpha, we provide direct evidence that YY1 and ATF6 are required for optimal stress induction of Grp78. We also discovered enhancement of the ER-stressed induction of the Grp78 promoter through the interaction of YY1 with the arginine methyltransferase PRMT1 and evidence of its action through methylation of the arginine 3 residue on histone H4. Furthermore, we detected ER stress-induced binding of the histone acetyltransferase p300 to the Grp78 promoter and histone H4 acetylation. A model for the ER stress-mediated transcription factor binding and chromatin modifications at the Grp78 promoter leading to its activation is proposed.