Dual regulation of cadmium-induced apoptosis by mTORC1 through selective induction of IRE1 branches in unfolded protein response.
Dual regulation of cadmium-induced apoptosis by mTORC1 through selective induction of IRE1 branches in unfolded protein response.
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DOI：
10.1371/journal.pone.0064344
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kitamura M
中科院分区：
文献类型：
--
作者：
Kato H;Katoh R;Kitamura M
镉(Cd)可引起活性氧(ROS)的产生，从而引发肾小管损伤。我们发现mTORC1的抑制剂雷帕霉素能减弱Cd诱导的肾小管上皮细胞的凋亡。敲除mTORC1的正向调节因子Raptor也有类似的效果。然而，雷帕霉素并没有改变ROS的产生，这表明mTORC1是ROS下游的靶标。事实上，ROS引起mTORC1的激活，这有助于诱导未折叠蛋白反应(UPR)的一个选择性分支，即IRE1途径。虽然Cd触发了三个主要的UPR通路，但Cd激活mTORC1后并不能诱导PERK-eIF2α和ATF6通路的产生。始终如一的是，基因敲除Raptor可以在不影响PERK-eIF2α通路的情况下抑制镉暴露细胞中的jnk。敲除mTORC1的负调控因子TSC2可激活mTORC1，增强Cd诱导的IRE1-JNK通路和细胞凋亡，但不影响其他UPR分支。抑制IRE1JNKK导致Cd处理的细胞α活性和细胞凋亡受到抑制。显性-负性抑制JNK也能抑制Cd诱导的细胞凋亡。相反，抑制IRE1XBP1内切核糖核酸酶活性或下游XBP1后，Cd诱导的细胞凋亡略有增加。在体内，给予雷帕霉素抑制镉处理小鼠肾脏中mTORC1JNK的激活，但不抑制eIF2α的激活。与肾小管损伤程度减轻及肾小管细胞凋亡性死亡有关。这些结果阐明了mTORC1通过选择性诱导IRE1信号通路对Cd所致肾损伤的双重调节作用。
Cadmium (Cd) causes generation of reactive oxygen species (ROS) that trigger renal tubular injury. We found that rapamycin, an inhibitor of mTORC1, attenuated Cd-induced apoptosis in renal tubular cells. Knockdown of Raptor, a positive regulator of mTORC1, also had the similar effect. However, rapamycin did not alter generation of ROS, suggesting that mTORC1 is a target downstream of ROS. Indeed, ROS caused activation of mTORC1, which contributed to induction of a selective branch of the unfolded protein response (UPR); i.e., the IRE1 pathway. Although Cd triggered three major UPR pathways, activation of mTORC1 by Cd did not contribute to induction of the PERK–eIF2α and ATF6 pathways. Consistently, knockdown of Raptor caused suppression of JNK without affecting the PERK–eIF2α pathway in Cd-exposed cells. Knockdown of TSC2, a negative regulator of mTORC1, caused activation of mTORC1 and enhanced Cd induction of the IRE1–JNK pathway and apoptosis without affecting other UPR branches. Inhibition of IRE1α kinase led to suppression of JNK activity and apoptosis in Cd-treated cells. Dominant-negative inhibition of JNK also suppressed Cd-induced apoptosis. In contrast, inhibition of IRE1α endoribonuclease activity or downstream XBP1 modestly enhanced Cd-induced apoptosis. In vivo, administration with rapamycin suppressed activation of mTORC1 and JNK, but not eIF2α, in the kidney of Cd-treated mice. It was correlated with attenuation of tubular injury and apoptotic cell death in the tubules. These results elucidate dual regulation of Cd-induced renal injury by mTORC1 through selective induction of IRE1 signaling.
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影响因子：
7.4
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Chen, Long;Xu, Baoshan;Liu, Lei;Luo, Van;Zhou, Hongyu;Chen, Wenxing;Shen, Tao;Han, Xiuzhen;Kontos, Christopher D.;Huang, Shile
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