Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response
Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response
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DOI：
10.1042/0264-6021:3550019
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发表时间：
2001-04-01
影响因子：
4.1
通讯作者：
Mori, K
中科院分区：
文献类型：
--
作者：
Haze, K;Okada, T;Mori, K
真核细胞通过一种称为未折叠蛋白反应(UPR)的转录诱导过程来控制内质网(ER)中分子伴侣和折叠酶的水平。哺乳动物的UPR是由19个核苷酸组成的顺式作用内质网应激反应元件(CCAATN(9)CCACG)介导的，CCACG部分被认为是提供特异性的。我们最近鉴定了碱性亮氨酸拉链(BZIP)蛋白ATF6是哺乳动物UPR特异的转录因子；ATF6被内质网应激诱导的蛋白分解激活并直接与CCACG结合。在此，我们报道了真核细胞表达的另一种在结构和功能上与ATF6密切相关的bZIP蛋白。这种由G13(cAMP反应元件结合蛋白相关蛋白)基因编码的蛋白质被结构性地合成为锚定在内质网膜上的II型跨膜糖蛋白，并在内质网应激下加工成可溶性形式，就像ATF6一样。ATF6和G13基因产物的蛋白降解过程伴随着它们从内质网到核的重新定位：它们的碱性区域似乎起着核定位信号的作用，G13产物的可溶性形式的过度表达结构性地激活了UPR，而缺乏激活结构域的突变体的过度表达则表现出强烈的显性-负效应。此外，ATF6的可溶性形式和G13基因产物在体外不能与几个顺式作用的内质网应激反应元件的点突变结合，这些突变体在体内几乎不能对内质网应激做出反应。因此，我们得出结论，这两个相关的bZIP蛋白是哺乳动物UPR的关键转录调控蛋白，并建议将ATF6基因产物ATF6α酸称为G13基因产物ATF6β。
Eukaryotic cells control the levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) by a transcriptional induction process termed the unfolded protein response (UPR). The mammalian UPR is mediated by the cis-acting ER stress response element consisting of 19 nt (CCAATN(9)CCACG), the CCACG part of which is considered to provide specificity. We recently identified the basic leucine zipper (bZIP) protein ATF6 as a mammalian UPR-specific transcription factor; ATF6 is activated by ER stress-induced proteolysis and binds directly to CCACG. Here we report that eukaryotic cells express another bZIP protein closely related to ATF6 in both structure and function. This protein encoded by the G13 (cAMP response element binding protein-related protein) gene is constitutively synthesized as a type II transmembrane glycoprotein anchored in the ER membrane and processed into a soluble form upon ER stress as occurs with ATF6. The proteolytic processing of ATF6 and the G13 gene product is accompanied by their relocation from the ER to the nucleus: their basic regions seem to function as a nuclear localization signal, Overexpression of the soluble form of the G13 product constitutively activates the UPR, whereas overexpression of a mutant lacking the activation domain exhibits a strong dominant-negative effect. Furthermore, the soluble forms of ATF6 and the G13 gene product are unable to bind to several point mutants of the cis-acting ER stress response element in vitro that hardly respond to ER stress in vivo. We thus concluded that the two related bZIP proteins are crucial transcriptional regulators of the mammalian UPR, and propose calling the ATF6 gene product ATF6 alpha acid the G13 gene product ATF6 beta.