Trafficking of the bZIP transmembrane transcription factor CREB-H into alternate pathways of ERAD and stress-regulated intramembrane proteolysis
Trafficking of the bZIP transmembrane transcription factor CREB-H into alternate pathways of ERAD and stress-regulated intramembrane proteolysis
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DOI：
10.1111/j.1600-0854.2007.00654.x
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发表时间：
2007-12-01
期刊：
影响因子：
4.5
通讯作者：
O'Hare, Peter
中科院分区：
文献类型：
--
作者：
Bailey, Daniel;Barreca, Cristina;O'Hare, Peter
CREB-H 是一种 ATF6 相关跨膜转录因子，响应内质网 (ER) 相关应激，被高尔基体蛋白酶切割并转运至细胞核以实现适当的适应性反应。我们描述了 CREB-H 的 ER 加工和周转，结果对 ER 应激调节和信号传导具有重要意义。我们证明 CREB-H 是糖基化的，并证明 CREB-H 的 ER 和核形式的半衰期都很短。我们还表明，CREB-H 通过 ER 相关降解 (ERAD) 途径经历逆转位、去糖基化和降解的循环。蛋白酶体抑制导致胞质中间体的积累，但与糖基化抑制相反，蛋白酶体抑制还促进 CREB-H 的特异性切割和 N 末端截短产物的核转运。我们的数据表明，在正常条件下，CREB-H 从 ER 转运回胞质溶胶，在那里它受到 ERAD 的影响，但在抑制蛋白酶体功能或促进负载的条件下，CREB-H 从此途径转移，而不是经历裂解和核转运。最后，我们确定了参与 CREB-H ER 保留的细胞质决定簇，其缺失会导致组成型高尔基体运输和相应的裂解。我们提出了一个模型，其中基本和亮氨酸拉链结构域跨膜蛋白的不同成员可以在不同水平上感知细胞应激。
CREB-H is an ATF6-related, transmembrane transcription factor that, in response to endoplasmic reticulum (ER)-associated stress, is cleaved by Golgi proteases and transported to the nucleus to effect appropriate adaptive responses. We characterize the ER processing and turnover of CREB-H with results which have important implications for ER stress regulation and signalling. We show that CREB-H is glycosylated and demonstrate that both the ER and nuclear forms of CREB-H have short half-lives. We also show that CREB-H is subject to cycles of retrotranslocation, deglycosylation and degradation through the ER-associated degradation (ERAD) pathway. Proteasome inhibition resulted in accumulation of a cytosolic intermediate but additionally, in contrast to inhibition of glycosylation, promoted specific cleavage of CREB-H and nuclear transport of the N-terminal-truncated product. Our data indicate that under normal conditions CREB-H is transported back from the ER to the cytosol, where it is subject to ERAD, but under conditions that repress proteasome function or promote load CREB-H is diverted from this pathway instead undergoing cleavage and nuclear transport. Finally, we identify a cytoplasmic determinant involved in CREB-H ER retention, deletion of which results in constitutive Golgi transport and corresponding cleavage. We present a model where cellular stresses may be sensed at different levels by different members of the basic and leucine zipper domain transmembrane proteins.