Bax inhibitor-1 regulates endoplasmic reticulum stress-associated reactive oxygen species and heme oxygenase-1 expression
Bax inhibitor-1 regulates endoplasmic reticulum stress-associated reactive oxygen species and heme oxygenase-1 expression
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DOI：
10.1074/jbc.m700053200
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发表时间：
2007-07-27
影响因子：
4.8
通讯作者：
Chae, Han-Jung
中科院分区：
文献类型：
--
作者：
Lee, Geum-Hwa;Kim, Hyun-Kyung;Chae, Han-Jung
Bax 抑制剂-1 (BI-1) 是一种抗凋亡蛋白，位于内质网 (ER) 膜上，可保护细胞免受 ER 应激诱导的细胞凋亡。 ER 与通过氧化蛋白质折叠产生活性氧 (ROS) 相关。本研究探讨了 BI-1 在调节 ER 应激诱导的 ROS 积累和未折叠蛋白反应相关蛋白表达中的作用。 BI-1 降低葡萄糖反应蛋白 78、C/EBP 同源蛋白、磷酸真核起始因子 2 α、IRE1 α、XBP-1 和磷酸-JNK 的表达水平，并抑制 ATF-6 α p-90 的裂解，从而抑制 ROS。尽管ROS清除剂对内质网应激诱导的细胞凋亡提供了一些保护，但促凋亡内质网应激蛋白的表达并未受到影响。这项研究表明，在内质网应激下，未折叠蛋白的反应伴随着 ROS 的积累，这在 BI-1 细胞中受到调节。这些BI-1相关功能的机制涉及通过核因子红细胞2相关因子2表达血红素加氧酶-1 (HO-1)。在BI-1细胞中，HO-1小干扰RNA的转染完全消除了BI-1诱导的保护作用。 HO-1 通过内质网应激引发的 ROS 内源性表达被认为是一种保护信号。总之，这些观察结果表明，BI-1 可以抑制 ER 应激蛋白以及 ROS 的积累，从而保护细胞。此外，HO-1 在 BI-1 相关的针对 ER 应激的保护中发挥着重要作用。
The Bax inhibitor-1 ( BI-1) is an anti-apoptotic protein that is located in endoplasmic reticulum (ER) membranes and protects cells from ER stress-induced apoptosis. The ER is associated with generation of reactive oxygen species (ROS) through oxidative protein folding. This study examined the role of BI-1 in the regulation of ER stress-induced accumulation of ROS and expression of unfolded protein response-associated proteins. BI-1 reduced the expression levels of glucose response protein 78, C/EBP homologous protein, phospho-eukaryotic initiation factor 2 alpha, IRE1 alpha, XBP-1, and phospho-JNK and inhibited the cleavage of ATF-6 alpha p-90, leading to the inhibition of ROS. Although ROS scavengers offer some protection against ER stress-induced apoptosis, the expression of pro-apoptotic ER stress proteins was not affected. This study shows that the response of unfolded proteins is followed by ROS accumulation under ER stress, which is regulated in BI-1 cells. The mechanism for these BI-1-associated functions involves the expression of heme oxygenase-1 (HO-1) through nuclear factor erythroid 2-related factor 2. In BI-1 cells, the transfection of HO-1 small interfering RNA completely abolished the BI-1-induced protection. The endogenous expression of HO-1 through ER stress-initiated ROS is believed to be as a protection signal. In conclusion, these observations suggest that BI-1 can inhibit the ER stress proteins as well as the accumulation of ROS, thereby protecting the cells. Moreover, HO-1 plays an important role in the BI-1-associated protection against ER stress.