Redox-assisted regulation of Ca^sup 2+^ homeostasis in the endoplasmic reticulum by disulfide reductase ERdj5

Calcium ion (Ca^sup 2+^) is an important second messenger that regulates numerous cellular functions. Intracellular Ca^sup 2+^ concentration ([Ca^sup 2+^]i) is strictly controlled by Ca^sup 2+^ channels and pumps on the endoplasmic reticulum (ER) and plasma membranes. The ER calcium pump, sarco/endo...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2016-10, Vol.113 (41), p.E6055
Main Authors: Ushioda, Ryo, Miyamoto, Akitoshi, Inoue, Michio, Watanabe, Satoshi, Okumura, Masaki, Maegawa, Ken-ichi, Uegaki, Kaiku, Fujii, Shohei, Fukuda, Yasuko, Umitsu, Masataka, Takagi, Junichi, Inaba, Kenji, Mikoshiba, Katsuhiko, Nagata, Kazuhiro
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Calcium
Endoplasmic reticulum
Homeostasis
Membranes
Plasma
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Summary:Calcium ion (Ca^sup 2+^) is an important second messenger that regulates numerous cellular functions. Intracellular Ca^sup 2+^ concentration ([Ca^sup 2+^]i) is strictly controlled by Ca^sup 2+^ channels and pumps on the endoplasmic reticulum (ER) and plasma membranes. The ER calcium pump, sarco/endoplasmic reticulum calcium ATPase (SERCA), imports Ca^sup 2+^ 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 [Ca^sup 2+^] ([Ca^sup 2+^]^sub ER^), whereas a higher [Ca^sup 2+^]^sub ER^ induced ERdj5 to form oligomers that were no longer able to interact with the pump, suggesting [Ca^sup 2+^]^sub 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, Ca^sup 2+^, and protein homeostasis in the ER.
ISSN:0027-8424
1091-6490