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.
(© 2023. The Author(s).)