Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress
Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress
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DOI：
10.7554/elife.11880
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发表时间：
2016-07-20
期刊：
影响因子：
7.7
通讯作者：
Walter, Peter
中科院分区：
文献类型：
--
作者：
Gallagher, Ciara M.;Walter, Peter
膜结合转录因子ATF6 α在内质网（ER）应激期间通过蛋白水解被激活。ATF6 α靶基因编码折叠酶、分子伴侣和脂质生物合成酶，这些酶响应需求增加蛋白质折叠能力。ATF6 α的关闭状态通过其在ER中与激活其的高尔基体驻留蛋白酶的空间分离来维持。我们发现Ceapins，一类吡唑酰胺，作为ATF6 α信号传导的选择性抑制剂，不抑制高尔基蛋白酶或其他UPR分支。我们发现Ceapins通过将其捕获在排除在ER出口位点之外的ER驻留病灶中来阻断ATF6 α信号传导。通过药理学消除ER和高尔基体的空间分离来消除对运输的要求，在Ceapins存在下恢复了ATF 6 α的切割。Ceapins的洗脱使ATF6 α对ER应激再敏感。这些结果表明，ATF6 α的运输受其寡聚状态的调节。
The membrane-bound transcription factor ATF6 alpha is activated by proteolysis during endoplasmic reticulum (ER) stress. ATF6 alpha target genes encode foldases, chaperones, and lipid biosynthesis enzymes that increase protein-folding capacity in response to demand. The off-state of ATF6 alpha is maintained by its spatial separation in the ER from Golgi-resident proteases that activate it. ER stress induces trafficking of ATF6 alpha. We discovered Ceapins, a class of pyrazole amides, as selective inhibitors of ATF6 alpha signaling that do not inhibit the Golgi proteases or other UPR branches. We show that Ceapins block ATF6 alpha signaling by trapping it in ER-resident foci that are excluded from ER exit sites. Removing the requirement for trafficking by pharmacological elimination of the spatial separation of the ER and Golgi apparatus restored cleavage of ATF6 alpha in the presence of Ceapins. Washout of Ceapins resensitized ATF6 alpha to ER stress. These results suggest that trafficking of ATF6 alpha is regulated by its oligomeric state.