ER Ca(2+) overload activates the IRE1α signaling and promotes cell survival.
ER Ca(2+) overload activates the IRE1α signaling and promotes cell survival.
复制标题
DOI：
10.1186/s13578-023-01062-y
复制
发表时间：
2023-07-03
影响因子：
7.5
通讯作者：
Tang, Tie-Shan
中科院分区：
文献类型：
--
作者：
Zhao, Song;Feng, Haiping;Jiang, Dongfang;Yang, Keyan;Wang, Si-Tong;Zhang, Yu-Xin;Wang, Yun;Liu, Hongmei;Guo, Caixia;Tang, Tie-Shan
维持内质网（ER）中Ca2+储存的稳态对于适当的Ca2+信号传导和关键细胞功能至关重要。虽然已知Ca2+耗竭会导致ER应激，进而激活未折叠蛋白反应（UPR），但当ER储存过载时，UPR传感器/转换器如何响应过量的Ca2+仍不清楚。在此，我们首次报道了ER Ca 2+超载可以直接敏化IRE1 α-XBP1轴。TMCO 1缺陷细胞中ER Ca 2+超载可导致BiP从IRE 1 α上解离，促进IRE 1 α蛋白的二聚化和稳定性，并促进IRE 1 α活化。有趣的是，通过IRE1 α抑制剂减弱过度活化的IRE1 α-XBP1s信号传导可导致TMCO 1缺陷细胞中的显著细胞死亡。我们的数据建立了ER中过量Ca2+与IRE1 α-XBP1轴选择性激活之间的因果关系，强调了ER Ca2+过载在IRE1 α激活和防止细胞死亡中的意想不到的作用。在线版本包含补充材料，可通过10.1186/s13578 - 023 - 01062-y获得。
Maintaining homeostasis of Ca2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca2+ signaling and key cellular functions. Although Ca2+ depletion has been known to cause ER stress which in turn activates the unfolded protein response (UPR), how UPR sensors/transducers respond to excess Ca2+ when ER stores are overloaded remain largely unclear. Here, we report for the first time that overloading of ER Ca2+ can directly sensitize the IRE1α-XBP1 axis. The overloaded ER Ca2+ in TMCO1-deficient cells can cause BiP dissociation from IRE1α, promote the dimerization and stability of the IRE1α protein, and boost IRE1α activation. Intriguingly, attenuation of the over-activated IRE1α-XBP1s signaling by a IRE1α inhibitor can cause a significant cell death in TMCO1-deficient cells. Our data establish a causal link between excess Ca2+ in ER stores and the selective activation of IRE1α-XBP1 axis, underscoring an unexpected role of overload of ER Ca2+ in IRE1α activation and in preventing cell death. The online version contains supplementary material available at 10.1186/s13578-023-01062-y.
登录
查看更多内容
影响因子：
5.6
作者：
通讯作者：
--
影响因子：
9
作者：
Yang, Ke-Yan;Zhao, Song;Feng, Haiping;Shen, Jiaqi;Chen, Yuwei;Wang, Si-Tong;Wang, Si-Jia;Zhang, Yu-Xin;Wang, Yun;Guo, Caixia;Liu, Hongmei;Tang, Tie-Shan
通讯作者：
Tang, Tie-Shan
影响因子：
7.7
作者：
Carrara M;Prischi F;Nowak PR;Kopp MC;Ali MM
通讯作者：
Ali MM
影响因子：
4.8
作者：
Ding, Wen-Xing;Ni, Hong-Min;Yin, Xiao-Ming
通讯作者：
Yin, Xiao-Ming
影响因子：
64.5
作者：
Amin-Wetzel N;Saunders RA;Kamphuis MJ;Rato C;Preissler S;Harding HP;Ron D
通讯作者：
Ron D