Reduction of disulfide bridges in the lumenal domain of ATF6 in response to glucose starvation
Reduction of disulfide bridges in the lumenal domain of ATF6 in response to glucose starvation
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DOI：
10.1247/csf.06024
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发表时间：
2006-01-01
影响因子：
1.5
通讯作者：
Mori, Kazutoshi
中科院分区：
文献类型：
--
作者：
Nadanaka, Satomi;Yoshida, Hiderou;Mori, Kazutoshi
哺乳动物转录因子ATF6是组成型合成的II型跨膜蛋白，嵌入内质网（ER）中。在ER应激时，ATF 6被转运到高尔基体，在高尔基体中被切割以释放其胞质结构域。然后转移到细胞核中，在那里它激活ER定位的分子伴侣和折叠酶的转录，以维持ER的稳态。我们最近发现，由于分子内和分子间二硫键的存在，ATF 6在未应激的ER中以单体、二聚体和寡聚体的形式存在。二硫键结合的ATF6在用各种化学ER应激诱导剂处理细胞时被还原，并且只有还原的单体ATF6到达高尔基体。在这项研究中，我们诱发ER应力在更多的生理条件下，即，葡萄糖饥饿，并分析其后果ATF6激活。葡萄糖饥饿激活ATF 6并诱导ER伴侣BiP，尽管很弱。因此，ATF6从BiP解离，运输到高尔基体，并被切割。葡萄糖饥饿增强合成的ATF6约2倍，可能是通过转录诱导。重要的是，二硫桥的还原和还原单体的运输发生在响应葡萄糖饥饿。我们的结论是ER应力诱导的ATF6减少代表了ATF6激活过程的一般特征。
Mammalian transcription factor ATF6 is constitutively synthesized as a type II transmembrane protein embedded in the endoplasmic reticulum (ER). Upon ER stress ATF6 is transported to the Golgi apparatus where it is cleaved to release its cytoplasmic domain. This is then translocated into the nucleus where it activates transcription of ER-localized molecular chaperones and folding enzymes to maintain the homeostasis of the ER. We recently found that, owing to the presence of intra- and intermolecular disulfide bridges, ATF6 occurs in unstressed ER in monomer, dimer and oligomer forms. Disulfide-bonded ATF6 is reduced on treatment of cells with various chemical ER stress inducers, and only the reduced monomer ATF6 reaches the Golgi apparatus. In this study, we evoked ER stress under more physiological conditions, namely, glucose starvation, and analyzed its consequence for ATF6 activation. Glucose starvation activated ATF6 and induced the ER chaperone BiP, albeit weakly. ATF6 was thus dissociated from BiP, transported to the Golgi apparatus, and cleaved. Glucose starvation enhanced the synthesis of ATF6 approximately two-fold, probably via transcriptional induction. Importantly, reduction of disulfide bridges and transport of reduced monomer occurred in response to glucose starvation. We conclude that ER stress-induced reduction of ATF6 represents a general feature of the ATF6 activation process.