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First published online October 22, 2008
doi: 10.1242/10.1242/jcs.028654

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Overexpressed cyclophilin B suppresses apoptosis associated with ROS and Ca²⁺ homeostasis after ER stress

Wonchae Choe^1,*

Sung Soo Kim^1,*

¹ Department of Biochemistry and Molecular Biology, Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species, BK-21, School of Medicine, Kyung Hee University, Seoul 130-701, Korea
² Department of Molecular and Cellular Biochemistry, Kangwon National University College of Medicine, Chunchon, Kangwon-do 200-701, Korea
³ Department of Biological Sciences, Bio/Molecular Informatics Center and Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Korea
⁴ Howard Hughes Medical Institute and Departments of Biological Chemistry and Internal Medicine, University of Michigan, 1150 W. Medical Center Dr, Ann Arbor, Michigan 48109, USA
⁵ Department of Biomedical Laboratory Science, Dongseo University, Busan 617-716, Korea

^* Author for cerrespondence (e-mail: wchoe{at}khu.ac.kr)

^* Author for cerrespondence (e-mail: sgskim{at}khu.ac.kr)

Accepted 9 July 2008

Prolonged accumulation of misfolded proteins in the endoplasmic reticulum (ER) results in ER stress-mediated apoptosis. Cyclophilins are protein chaperones that accelerate the rate of protein folding through their peptidyl-prolyl cis-trans isomerase (PPIase) activity. In this study, we demonstrated that ER stress activates the expression of the ER-localized cyclophilin B (CypB) gene through a novel ER stress response element. Overexpression of wild-type CypB attenuated ER stress-induced cell death, whereas overexpression of an isomerase activity-defective mutant, CypB/R62A, not only increased Ca²⁺ leakage from the ER and ROS generation, but also decreased mitochondrial membrane potential, resulting in cell death following exposure to ER stress-inducing agents. siRNA-mediated inhibition of CypB expression rendered cells more vulnerable to ER stress. Finally, CypB interacted with the ER stress-related chaperones, Bip and Grp94. Taken together, we concluded that CypB performs a crucial function in protecting cells against ER stress via its PPIase activity.

Key words: Cyclophilin B, Endoplasmic reticulum stress, Peptidyl prolyl cis-trans isomerase (Pplase), Reactive oxygen species (ROS)