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

Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6055-E6063. doi: 10.1073/pnas.1605818113. Epub 2016 Sep 30.


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.

Keywords: ERdj5; SERCA2; calcium homeostasis; endoplasmic reticulum; redox regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Signaling
  • Cell Line
  • Endoplasmic Reticulum / metabolism*
  • Enzyme Activation
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • HSP40 Heat-Shock Proteins / chemistry
  • HSP40 Heat-Shock Proteins / genetics
  • HSP40 Heat-Shock Proteins / metabolism*
  • Homeostasis*
  • Humans
  • Mice
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Oxidation-Reduction*
  • Protein Binding
  • Protein Multimerization
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Recombinant Proteins
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics


  • ERdj5 protein, mouse
  • HSP40 Heat-Shock Proteins
  • Molecular Chaperones
  • RNA, Small Interfering
  • Recombinant Proteins
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • ATP2A2 protein, human
  • Calcium