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

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.