ER Ca2+ overload activates the IRE1α signaling and promotes cell survival

Cell & Bioscience

Research

Caixia Guo¹  Yun Wang²  Hongmei Liu³  Tie-Shan Tang⁴  Yu-Xin Zhang⁵  Haiping Feng⁵  Song Zhao⁵  Dongfang Jiang⁵  Si-Tong Wang⁵  Keyan Yang⁵ 

[1] Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, 100101, Beijing, China;University of Chinese Academy of Sciences, 100049, Beijing, China;State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China;State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China;Beijing Institute for Stem Cell and Regenerative Medicine, 100101, Beijing, China;State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China;Beijing Institute for Stem Cell and Regenerative Medicine, 100101, Beijing, China;University of Chinese Academy of Sciences, 100049, Beijing, China;State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China;University of Chinese Academy of Sciences, 100049, Beijing, China;

关键词: ER Ca overload;    TMCO1;    ER stress;    IRE1α;   

DOI  :  10.1186/s13578-023-01062-y

 received in 2023-02-10, accepted in 2023-05-26,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMaintaining 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.ResultsHere, 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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