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

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

Author information

1
Laboratory of Molecular and Cellular Biology, Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan; Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto 603-8555, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan.
2
Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
3
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan; Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai 980-8577, Japan.
4
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai 980-8577, Japan.
5
Laboratory of Molecular and Cellular Biology, Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan.
6
Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Suita 565-0871, Osaka, Japan.
7
Laboratory of Molecular and Cellular Biology, Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan; Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto 603-8555, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan; nagata@cc.kyoto-su.ac.jp.

Abstract

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

PMID:
27694578
PMCID:
PMC5068290
DOI:
10.1073/pnas.1605818113
[Indexed for MEDLINE]
Free PMC Article

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