ER Ca2+ overload activates the IRE1[alpha] signaling and promotes cell survival

Maintaining homeostasis of Ca.sup.2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca.sup.2+ signaling and key cellular functions. Although Ca.sup.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.sup.2+ when ER stores are overloaded remain largely unclear. Here, we report for the first time that overloading of ER Ca.sup.2+ can directly sensitize the IRE1[alpha]-XBP1 axis. The overloaded ER Ca.sup.2+ in TMCO1-deficient cells can cause BiP dissociation from IRE1[alpha], promote the dimerization and stability of the IRE1[alpha] protein, and boost IRE1[alpha] activation. Intriguingly, attenuation of the over-activated IRE1[alpha]-XBP1s signaling by a IRE1[alpha] inhibitor can cause a significant cell death in TMCO1-deficient cells. Our data establish a causal link between excess Ca.sup.2+ in ER stores and the selective activation of IRE1[alpha]-XBP1 axis, underscoring an unexpected role of overload of ER Ca.sup.2+ in IRE1[alpha] activation and in preventing cell death.