ER Ca 2+ overload activates the IRE1α signaling and promotes cell survival
Cell & bioscience(2023)
摘要
Background Maintaining homeostasis of Ca 2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca 2+ signaling and key cellular functions. Although Ca 2+ depletion has been known to cause ER stress which in turn activates the unfolded protein response (UPR), how UPR sensors/transducers respond to excess Ca 2+ when ER stores are overloaded remain largely unclear. Results Here, we report for the first time that overloading of ER Ca 2+ can directly sensitize the IRE1α-XBP1 axis. The overloaded ER Ca 2+ 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. Conclusions Our data establish a causal link between excess Ca 2+ in ER stores and the selective activation of IRE1α-XBP1 axis, underscoring an unexpected role of overload of ER Ca 2+ in IRE1α activation and in preventing cell death.
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关键词
ER Ca 2+ overload
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