ERp29 deficiency affects sensitivity to apoptosis via impairment of the ATF6-CHOP pathway of stress response
ERp29 deficiency affects sensitivity to apoptosis via impairment of the ATF6-CHOP pathway of stress response
复制标题
DOI：
10.1007/s10495-013-0961-0
复制
发表时间：
2014-05-01
期刊：
影响因子：
7.2
通讯作者：
Ferrari, David Michael
中科院分区：
文献类型：
--
作者：
Hirsch, Irina;Weiwad, Matthias;Ferrari, David Michael
内质网蛋白29（ERp 29）属于无氧化还原活性的PDI-D β-亚家族的PDI蛋白。ERp 29在所有检查的哺乳动物组织中表达。在分泌组织和一些肿瘤中观察到特别高的表达水平。然而，ERp 29的生物学作用仍不清楚。在本研究中，我们通过使用成年ERp 29（-/-）小鼠的甲状腺细胞和原代真皮成纤维细胞显示，ERp 29缺陷影响未折叠蛋白反应（UPR）的ATF 6-CHOP分支的激活，而不影响其他UPR分支的功能，如ATF 4-eIF 2 α-XBP 1信号通路。由于ATF 6活化受损，当用衣霉素和过氧化氢处理时，来自ERp 29（-/-）小鼠的真皮成纤维细胞和成年甲状腺细胞显示出显著较低的凋亡敏感性。然而，与以前的报道相反，我们可以证明，ERp 29缺陷不改变甲状腺球蛋白的表达水平。因此，我们的研究表明，ERp 29作为一个护送因子ATF 6，并促进其运输从ER高尔基体在ER应激条件下。
Endoplasmic reticulum protein 29 (ERp29) belongs to the redox-inactive PDI-D beta-subfamily of PDI-proteins. ERp29 is expressed in all mammalian tissues examined. Especially high levels of expression were observed in secretory tissues and in some tumors. However, the biological role of ERp29 remains unclear. In the present study we show, by using thyrocytes and primary dermal fibroblasts from adult ERp29(-/-) mice, that ERp29 deficiency affects the activation of the ATF6-CHOP-branch of unfolded protein response (UPR) without influencing the function of other UPR branches, like the ATF4-eIF2 alpha-XBP1 signaling pathway. As a result of impaired ATF6 activation, dermal fibroblasts and adult thyrocytes from ERp29(-/-) mice display significantly lower apoptosis sensitivities when treated with tunicamycin and hydrogen peroxide. However, in contrast to previous reports, we could demonstrate that ERp29 deficiency does not alter thyroglobulin expression levels. Therefore, our study suggests that ERp29 acts as an escort factor for ATF6 and promotes its transport from ER to Golgi apparatus under ER stress conditions.