ATF6 Is a Transcription Factor Specializing in the Regulation of Quality Control Proteins in the Endoplasmic Reticulum
ATF6 Is a Transcription Factor Specializing in the Regulation of Quality Control Proteins in the Endoplasmic Reticulum
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DOI：
10.1247/csf.07044
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发表时间：
2008-01-01
影响因子：
1.5
通讯作者：
Mori, Kazutoshi
中科院分区：
文献类型：
--
作者：
Adachi, Yusuke;Yamamoto, Keisuke;Mori, Kazutoshi
真核细胞通过激活未折叠蛋白反应（UPR）来科普内质网（ER）应激，UPR是转录和翻译控制的协调系统，其确保合成蛋白的完整性。哺乳动物细胞在ER中表达三种UPR转导物，即IRE1、PERK和ATF6。IRE1途径从酵母到人类都是保守的，不仅介导ER质量控制蛋白（分子伴侣、折叠酶和ER相关降解的组分）的转录诱导，而且介导在分泌的各个阶段起作用的蛋白质的转录诱导。在后生动物细胞中保守的PERK途径负责翻译控制，并且还参与哺乳动物中的转录控制。ATF6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，在哺乳动物中由两种密切相关的因子ATF6 α和ATF6 β组成。ATF6 α而不是ATF6 β在转录控制中起重要作用。在这项研究中，我们在小鼠中对ATF6 α靶基因进行了全基因组搜索。在14，729个可分析的基因中，只有30个被鉴定为特异性靶标，其中40%是ER质量控制蛋白，20%是ER蛋白，而其余的具有各种功能。PERK的缺失对ER质量控制蛋白的转录诱导的负面影响可以通过其对ATF6 α激活的抑制作用来解释。此外，参与从ER转运的蛋白质不受ATF6 α调节，并且折叠的货物分子从ER的转运不受ATF6 α缺乏的影响。基于这些结果，我们提出ATF6是一个转录因子专门在ER质量控制蛋白的调节。
Eukaryotic cells cope with endoplasmic reticulum (ER) stress by activating the unfolded protein response (UPR), a coordinated system of transcriptional and translational controls, which ensures the integrity of synthesized proteins. Mammalian cells express three UPR transducers in the ER, namely IRE1, PERK and ATF6. The IRE1 pathway, which is conserved from yeast to humans, mediates transcriptional induction of not only ER quality control proteins ( molecular chaperones, folding enzymes and components of ER-associated degradation) but also proteins working at various stages of secretion. The PERK pathway, conserved in metazoan cells, is responsible for translational control and also participates in transcriptional control in mammals. ATF6 is an ER-membrane-bound transcription factor activated by ER stress-induced proteolysis which consists of two closely related factors, ATF6 alpha and ATF6 beta, in mammals. ATF6 alpha but not ATF6 beta plays an important role in transcriptional control. In this study, we performed a genome-wide search for ATF6 alpha-target genes in mice. Only 30 of the 14,729 analyzable genes were identified as specific targets, of which 40% were ER quality control proteins, 20% were ER proteins, while the rest had miscellaneous functions. The negative effects of the absence of PERK on transcriptional induction of ER quality control proteins could be explained by its inhibitory effect on ATF6 alpha activation. Further, proteins involved in transport from the ER are not regulated by ATF6 alpha, and transport of folded cargo molecules from the ER was not affected by the absence of ATF6 alpha. Based on these results, we propose that ATF6 is a transcription factor specialized in the regulation of ER quality control proteins.