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

Background 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.Results Here, we report for the first time that overloading of ER Ca2+ can directly sensitize the IRE1a-XBP1 axis. The overloaded ER Ca2+ in TMCO1-deficient cells can cause BiP dissociation from IRE1a, promote the dimerization and stability of the IRE1a protein, and boost IRE1a activation. Intriguingly, attenuation of the over-activated IRE1a-XBP1s signaling by a IRE1a inhibitor can cause a significant cell death in TMCO1-deficient cells.Conclusions Our data establish a causal link between excess Ca2+ in ER stores and the selective activation of IRE1a-XBP1 axis, underscoring an unexpected role of overload of ER Ca2+ in IRE1a activation and in preventing cell death.

Automated summary

This study reveals that excessive ER Ca2+ can directly activate the IRE1a-XBP1 pathway, and inhibition of over-activated IRE1a-XBP1 signaling in TMCO1-deficient cells can lead to significant cell death.