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

Abstract

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 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. Conclusions 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.

TMCO1 regulates cell proliferation, metastasis and EMT signaling through CALR, promoting ovarian cancer progression and cisplatin resistance

“…Our research demonstrates that TMCO1 regulated the expression of CALR, and this impact is consistent with variations in intracellular calcium ion concentrations. It has been reported that TMCO1 and CALR control cell proliferation and death, respectively, in order to maintain calcium homeostasis in the endoplasmic reticulum [35]. However, our results showed that TMCO1 silencing also inhibited cell proliferation and cytoskeletal reorganization in addition to lowering CALR expression.…”

Characterization of PDGF-Induced Subcellular Calcium Regulations through Calcium Channels in Airway Smooth Muscle Cells by FRET Biosensors

“…Cells have a certain self-protection mechanism, and when calcium overload occurs in the ER, certain pathways are activated to maintain intracellular calcium homeostasis [47,48]. In addition, we also observed changes in intracellular calcium signal flow after inhibiting IP3R, L-type calcium pathway, and SERCA calcium pump.…”

Characterization of PDGF-Induced Subcellular Calcium Regulation through Calcium Channels in Airway Smooth Muscle Cells by FRET Biosensors

“…Cells have a certain self-protection mechanism, and when a calcium overload occurs in the ER, certain pathways are activated to maintain the intracellular calcium homeostasis [48,49]. In addition, we observed changes in the intracellular calcium signal flow after inhibiting IP 3 R, the L-type calcium pathway, and the SERCA calcium pump.…”