Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response.
Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response.
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DOI：
10.1074/jbc.m003322200
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发表时间：
2000-09
期刊：
影响因子：
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通讯作者：
Yan Wang;Jingshi Shen;N. Arenzana;W. Tirasophon;R. Kaufman;R. Prywes
中科院分区：
文献类型：
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作者：
Yan Wang;Jingshi Shen;N. Arenzana;W. Tirasophon;R. Kaufman;R. Prywes
ATF 6是碱性亮氨酸拉链转录因子家族的成员。它含有一个跨膜结构域，位于内质网膜上。ATF 6与内质网（ER）应激反应途径有关，因为它可以激活由ER应激反应诱导的GRP 78和其他基因的表达。ER应激似乎通过从ER膜裂解并易位至细胞核来激活ATF 6。然而，ATF 6的直接DNA结合尚未得到证实。在这份报告中，我们已经确定了一个共识的DNA结合序列的ATF 6。该位点与ATF 1/CREB结合位点相关但不同。该位点位于报告基因中，并被ATF 6过表达特异性激活，并被ER应激反应强烈诱导。ATF 6的显性负性形式阻断了ATF 6位点和GRP 78报告基因的ER应激诱导。我们进一步发现GAL 4-ATF 6可以被ER应激激活。这些结果表明，ATF 6是ER应激反应的直接靶标。ER应激反应的近端传感器，人IRE 1（hIRE 1），足以激活ATF 6报告基因，而显性负性形式的hIRE 1阻断ER应激激活，表明hIRE 1是ER应激信号通路中ATF 6的上游。
ATF6 is a member of the basic-leucine zipper family of transcription factors. It contains a transmembrane domain and is located in membranes of the endoplasmic reticulum. ATF6 has been implicated in the endoplasmic reticulum (ER) stress response pathway since it can activate expression of GRP78 and other genes induced by the ER stress response. ER stress appears to activate ATF6 by cleavage from the ER membrane and translocation to the nucleus. However, direct DNA binding by ATF6 had not been demonstrated. In this report, we have identified a consensus DNA binding sequence for ATF6. This site is related to but distinct from ATF1/CREB binding sites. The site was placed in a reporter gene and was specifically activated by ATF6 overexpression and was strongly induced by the ER stress response. A dominant negative form of ATF6 blocked ER stress induction of both ATF6 site and GRP78 reporter genes. We further found that GAL4-ATF6 could be activated by ER stress. These results demonstrate that ATF6 is a direct target of the ER stress response. A proximal sensor of the ER stress response, human IRE1 (hIRE1), was sufficient to activate the ATF6 reporter gene, while a dominant negative form of hIRE1 blocked ER stress activation, suggesting that hIRE1 is upstream of ATF6 in the ER stress signaling pathway.