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 activity-dependent 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.

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