ER Ca(2+) overload activates the IRE1α signaling and promotes cell survival

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01062-y.