Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1.
Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1.
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发表时间：
2007
影响因子：
11.8
通讯作者：
Keisuke Yamamoto;Takashi Sato;Toshie Matsui;Masanori Sato;T. Okada;H. Yoshida;Akihiro Harada;Kazutoshi Mori
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文献类型：
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作者：
Keisuke Yamamoto;Takashi Sato;Toshie Matsui;Masanori Sato;T. Okada;H. Yoshida;Akihiro Harada;Kazutoshi Mori
后生动物普遍表达三种未折叠的蛋白质反应转导物（IRE 1、PERK和ATF 6）以科普内质网（ER）应激。ATF 6是一种由ER应激诱导的蛋白水解激活的ER膜结合转录因子，并已在哺乳动物中复制。在这里，我们产生了ATF 6 α和ATF 6 β敲除小鼠，它们发育正常，然后发现它们的双重敲除导致胚胎死亡。对缺乏ATF 6 α或ATF 6 β的小鼠胚胎成纤维细胞（MEF）的分析显示，ATF 6 α仅负责ER伴侣的转录诱导，并且ATF 6 α与XBP 1异二聚化以诱导ER相关降解组分。ATF 6 α（-/-）MEFs对内质网应激敏感。在ATF 6 β（-/-）MEFs中观察到的未改变的反应表明ATF 6 β不是ATF 6 α的负调节因子。这些结果表明，ATF 6 α在哺乳动物细胞中作为ER质量控制蛋白的关键调节剂发挥作用，与IRE 1负责的蠕虫和苍蝇细胞形成鲜明对比。
Metazoans express three unfolded protein response transducers (IRE1, PERK, and ATF6) ubiquitously to cope with endoplasmic reticulum (ER) stress. ATF6 is an ER membrane-bound transcription factor activated by ER stress-induced proteolysis and has been duplicated in mammals. Here, we generated ATF6alpha- and ATF6beta-knockout mice, which developed normally, and then found that their double knockout caused embryonic lethality. Analysis of mouse embryonic fibroblasts (MEFs) deficient in ATF6alpha or ATF6beta revealed that ATF6alpha is solely responsible for transcriptional induction of ER chaperones and that ATF6alpha heterodimerizes with XBP1 for the induction of ER-associated degradation components. ATF6alpha(-/-) MEFs are sensitive to ER stress. Unaltered responses observed in ATF6beta(-/-) MEFs indicate that ATF6beta is not a negative regulator of ATF6alpha. These results demonstrate that ATF6alpha functions as a critical regulator of ER quality control proteins in mammalian cells, in marked contrast to worm and fly cells in which IRE1 is responsible.