Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress
Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress
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哺乳动物转录因子 ATF6 以跨膜蛋白的形式合成，并在内质网应激时通过蛋白水解激活
DOI：
10.1091/mbc.10.11.3787
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发表时间：
1999-11-01
影响因子：
3.3
通讯作者：
Mori, K
中科院分区：
文献类型：
--
作者：
Haze, K;Yoshida, H;Mori, K
未折叠蛋白反应（UPR）控制内质网（ER）中参与蛋白质折叠的分子伴侣和酶的水平。我们最近分离了ATF 6作为哺乳动物UPR特异性转录因子的候选物。我们在这里报告，组成型表达为90 kDa的蛋白质（p90 ATF 6）直接转化为50 kDa的蛋白质（p50 ATF 6）在PR应激细胞。此外，我们还发现这种转变最重要的结果是改变了亚细胞定位; p90 ATF 6嵌入ER，而p50 ATF 6是一种核蛋白。p90 ATF 6是一种II型跨膜糖蛋白，分子中间有一段疏水链。因此，含有碱性亮氨酸拉链基序的N-末端的一半朝向细胞质。全长ATF 6及其携带跨膜结构域的C末端缺失突变体在转染时定位于ER中。相反，代表细胞质区域的突变ATF 6易位到细胞核中并激活内源GRP 78/BiP基因的转录。我们提出，ER应激诱导的蛋白水解膜结合的p90 ATF 6释放可溶性p50 ATF 6，导致在细胞核中诱导转录。与酵母UPR不同，哺乳动物UPR似乎使用类似于胆固醇稳态报告的系统。
The unfolded protein response (UPR) controls the levels of molecular chaperones and enzymes involved in protein folding in the endoplasmic reticulum (ER). We recently isolated ATF6 as a candidate for mammalian UPR-specific transcription factor. We report here that ATF6 constitutively expressed as a 90-kDa protein (p90ATF6) is directly converted to a 50-kDa protein (p50ATF6) in PR-stressed cells. Furthermore, we showed that the most important consequence of this conversion was altered subcellular localization; p90ATF6 is embedded in the ER, whereas p50ATF6 is a nuclear protein. p90ATF6 is a type II transmembrane glycoprotein with a hydrophobic stretch in the middle of the molecule. Thus, the N-terminal half containing a basic leucine zipper motif is oriented facing the cytoplasm. Full-length ATF6 as well as its C-terminal deletion mutant carrying the transmembrane domain is localized in the ER when transfected. In contrast, mutant ATF6 representing the cytoplasmic region translocates into the nucleus and activates transcription of the endogenous GRP78/BiP gene. We propose that ER stress-induced proteolysis of membrane-bound p90ATF6 releases soluble p50ATF6, leading to induced transcription in the nucleus. Unlike yeast UPR, mammalian UPR appears to use a system similar to that reported for cholesterol homeostasis.