Hydrogen peroxide triggers the proteolytic cleavage and the inactivation of calcineurin.
Increases in the levels of reactive oxygen species (ROS) are correlated with a decrease in calcineurin (CN) activity under oxidative or neuropathological conditions. However, the molecular mechanism underlying this ROS-mediated CN inactivation remains unclear. Here, we describe a mechanism for the inactivation of CN by hydrogen peroxide. The treatment of mouse primary cortical neuron cells with Abeta(1-42) peptide and hydrogen peroxide triggered the proteolytic cleavage of CN and decreased its enzymatic activity. In addition, hydrogen peroxide was found to cleave CN in different types of cells. Calcium influx was not involved in CN inactivation during hydrogen peroxide-mediated cleavage, but CN cleavage was partially blocked by chloroquine, indicating that an unidentified lysosomal protease is probably involved in its hydrogen peroxide-mediated cleavage. Treatment with hydrogen peroxide triggered CN cleavage at a specific sequence within its catalytic domain, and the cleaved form of CN had no enzymatic ability to dephosphorylate nuclear factor in activated T cells. Thus, our findings suggest a molecular mechanism by which hydrogen peroxide inactivates CN by proteolysis in ROS-related diseases.
Lee
Ji-Eun
JE
Department of Biochemistry and Molecular Biology, Cancer Research Institute, Interdisciplinary Program in Genetic Engineering, Seoul National University College of Medicine, Seoul, South Korea.
Kim
Hyungsoo
H
Jang
Hyonchol
H
Cho
Eun-Jung
EJ
Youn
Hong-Duk
HD
D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D016296:Mutagenesis / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D016877:Oxidants / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D016877:Oxidants; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D006861:Hydrogen Peroxide; D019703:Calcineurin