Redox-assisted regulation of Ca²⁺ homeostasis in the endoplasmic reticulum by disulfide reductase ERdj5

Calcium ion (Ca²⁺) is an important second messenger that regulates numerous cellular functions. Intracellular Ca²⁺ concentration ([Ca²⁺]i) is strictly controlled by Ca²⁺ channels and pumps on the endoplasmic reticulum (ER) and plasma membranes. The ER calcium pump, sarco/endoplasmic reticulum calcium ATPase (SERCA), imports Ca²⁺ from the cytosol into the ER in an ATPase activitydependent manner. The activity of SERCA2b, the ubiquitous isoform of SERCA, is negatively regulated by disulfide bond formation between two luminal cysteines. Here, we show that ERdj5, a mammalian ER disulfide reductase, which we reported to be involved in the ER-associated degradation of misfolded proteins, activates the pump function of SERCA2b by reducing its luminal disulfide bond. Notably, ERdj5 activated SERCA2b at a lower ER luminal [Ca²⁺] ([Ca²⁺]ER), whereas a higher [Ca²⁺]ER induced ERdj5 to form oligomers that were no longer able to interact with the pump, suggesting [Ca²⁺]ER-dependent regulation. Binding Ig protein, an ER-resident molecular chaperone, exerted a regulatory role in the oligomerization by binding to the J domain of ERdj5. These results identify ERdj5 as one of the master regulators of ER calcium homeostasis and thus shed light on the importance of cross talk among redox, Ca²⁺, and protein homeostasis in the ER.