STIMulating IRE1: How store-operated Ca2+ entry intersects with ER proteostasis

The endoplasmic reticulum (ER) controls intracellular Ca²⁺ dynamics. Depletion of ER Ca²⁺ stores results in short-term activation of store-operated Ca²⁺ entry (SOCE) via STIM1/Orai1 at ER-plasma membrane (ER-PM) contact sites (MCSs) and the long-term activation of the unfolded protein response (UPR), securing ER proteostasis. Recent work by Carreras-Sureda and colleagues describes a bidirectional control between IRE1 and STIM1 within the ER lumen that regulates ER-PM contact assembly and SOCE to sustain T-cell activation and myoblast differentiation.