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153. Mitogen-activated protein kinase-mediated phosphorylation of peroxiredoxin 6 regulates its phospholipase A(2) activity

Author

Wu, Yongzheng, Feinstein, Sheldon, Manevich, Yefim, Chowdhury, Ibrul, Pak, Jhang Ho, Kazi, Altaf, Dodia, Chandra, Speicher, David, Fisher, Aron, Feinstein, Sheldon I., Speicher, David W., Fisher, Aron B., Institute for Environmental Medicine [Philadelphia], University of Pennsylvania [Philadelphia], Wistar Institute [Philadelphia], This work was supported by grants from the National Institutes of Health [grant numbers HL19737 and HL79063]., We thank Susan Turbitt for typing the manuscript., and University of Pennsylvania

Subjects
Cell Extracts, Threonine, MESH: Pulmonary Alveoli, peroxidase, MESH: Rats, Sprague-Dawley, Mitogen-activated protein kinase kinase, MESH: Peroxiredoxin VI, Biochemistry, MAP2K7, lung surfactant, Rats, Sprague-Dawley, MESH: Cell Extracts, MESH: Protein Kinase Inhibitors, Protein phosphorylation, MESH: Animals, Electrophoresis, Gel, Two-Dimensional, deacylation–reacylation, MESH: Threonine, Phosphorylation, MESH: Phospholipases A2, Protein Kinase C, Kinase, peroxiredoxin, Endocytosis, MESH: Endocytosis, Tetradecanoylphorbol Acetate, lipids (amino acids, peptides, and proteins), Mitogen-Activated Protein Kinases, MESH: Mutation, MESH: Rats, Biology, granular pneumocyte, Article, Animals, Humans, Immunoprecipitation, Protein kinase A, Molecular Biology, Protein Kinase Inhibitors, Protein kinase C, phorbol ester, MESH: Tetradecanoylphorbol Acetate, MESH: Humans, MESH: Phosphorylation, MESH: Immunoprecipitation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: Electrophoresis, Gel, Two-Dimensional, Molecular biology, MESH: Protein Kinase C, MESH: Mitogen-Activated Protein Kinases, Rats, Pulmonary Alveoli, Phospholipases A2, MESH: Protein Processing, Post-Translational, Mutation, Peroxiredoxin, Protein Processing, Post-Translational, Peroxiredoxin VI
Abstract

Prdx6 (peroxiredoxin 6), a bifunctional protein with both GSH peroxidase and PLA2 (phospholipase A2) [aiPLA2 (acidic calcium-independent PLA2)] activities, is responsible for the metabolism of lung surfactant phospholipids. We propose that the aiPLA2 activity of the enzyme is regulated through phosphorylation. Incubation of isolated rat alveolar type II cells (AECII) with PMA, a PKC (protein kinase C) agonist, had no effect on Prdx6 expression but led to ∼75% increase in aiPLA2 activity that was abolished by pretreatment of cells with the MAPK (mitogen-activated protein kinase) inhibitors, SB202190 or PD98059. Prdx6 phosphorylation after incubation of AECII with PMA was demonstrated by autoradiography after immunoprecipitation with either anti-phosphothreonine o-phosphoserine antibodies. in vitro , several active isoforms of ERK (extracellular-signal-regulated kinase) and p38 phosphorylated Prdx6, resulting in an 11-fold increase in aiPLA2 activity. The increased activity was calcium-independent and was abolished by the aiPLA2 inhibitors, surfactant protein A and hexadecyl-3-trifluorethylglycero- sn -2-phospho-methanol (MJ33). The peroxidase activity of Prdx6 was unaffected by phosphorylation. Mass spectroscopic analysis of in vitro phosphorylated Prdx6 showed a unique phosphorylation site at Thr-177 and mutation of this residue abolished protein phosphorylation and the increase in MAPK-mediated activity. These results show that the MAPKs can mediate phosphorylation of Prdx6 at Thr-177 with a consequent marked increase in its aiPLA2 activity. Abbreviations: 2D, two-dimensional; [3H]DPPC, 1-palmitoyl-2-[3H]9,10-palmitoyl-sn-glycero-3-phosphorylcholine; AECII, alveolar epithelial type II cells; DEF domain, docking site of ERK FXF domain; ERK, extracellular-signal-regulated kinase; IEF, isoelectric focusing; IPG, immobilized pH gradient; JNK, c-Jun N-terminal kinase; PC, phosphatidylcholine; DPPC, dipalmitoyl phosphatidylcholine; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinase; MS/MS, tandem MS; pAb, polyclonal antibody; PKC, protein kinase C; PLA2, phospholipase A2; aiPLA2, acidic calcium-independent PLA2; PLPCOOH, phospholipid hydroperoxide; Prdx, peroxiredoxin; Sp-A, surfactant protein-A

Published
2009
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154. Oxidant Stress Stimulates Expression of the Human Peroxiredoxin 6 (Prdx6) Gene by a Transcriptional Mechanism Involving an Antioxidant Response Element

Author

Chowdhury, Ibrul, Mo, Yiqun, Gao, Ling, Kazi, Altaf, Fisher, Aron B., and Feinstein, Sheldon I.

Subjects
Male, Transcriptional Activation, NF-E2-Related Factor 2, Response Elements, Transfection, Article, Antioxidants, Cell Line, Rats, Sprague-Dawley, Animals, Humans, RNA, Small Interfering, Promoter Regions, Genetic, Lung, Sequence Deletion, Feedback, Physiological, Kelch-Like ECH-Associated Protein 1, Intracellular Signaling Peptides and Proteins, Epithelial Cells, Hydrogen Peroxide, respiratory system, Chromatin Assembly and Disassembly, Hydroquinones, Rats, Oxidative Stress, Basic-Leucine Zipper Transcription Factors, Enzyme Induction, Peroxiredoxin VI, Protein Binding
Abstract

Peroxiredoxin 6 (Prdx6) is a unique antioxidant enzyme that can reduce phospholipid and other hydroperoxides. A549 cells, a human lung-derived cell line, express both Prdx6 and Nrf2, a transcription factor that binds to antioxidant-response elements (AREs) and promotes expression of antioxidant genes. Treatment of A549 cells with 500 microM H(2)O(2) increased Prdx6 mRNA levels 2.5-fold, whereas treatment with 400 microM H(2)O(2) or 200 microM tert-butylhydroquinone (t-BHQ) triggered a corresponding 2.5-fold increase in reporter gene activity in A549 cells transfected with the pSEAP2:Basic vector (BD Bioscience), containing 1524 nucleotides of the human Prdx6 promoter region. Deletion of a consensus ARE sequence present between positions 357 and 349 before the start of transcription led to a striking decrease in both basal and H(2)O(2)- or t-BHQ-induced activation in A549 cells and H(2)O(2)-induced activation in primary rat alveolar type II cells. Cotransfection with Nrf2 stimulated the Prdx6 promoter in an ARE-dependent manner, whereas it was negatively regulated by Nrf3. siRNA targeting Nrf2 down-regulated reporter gene expression, whereas siRNA targeting the Nrf2 repressor, Keap1, up-regulated it. Binding of Nrf2 to the ARE sequence in chromatin was confirmed by PCR after chromatin immunoprecipitation. These data demonstrate that the ARE within the Prdx6 promoter is a key regulator of basal transcription of the Prdx6 gene and of its inducibility under conditions of oxidative stress.

Published
2008

167. Mechanotransduction Drives Post Ischemic Revascularization Through KATP Channel Closure and Production of Reactive Oxygen Species

Author

Browning, Elizabeth, primary, Wang, Hui, additional, Hong, Nankang, additional, Yu, Kevin, additional, Buerk, Donald G., additional, DeBolt, Kristine, additional, Gonder, Daniel, additional, Sorokina, Elena M., additional, Patel, Puja, additional, De Leon, Diva D., additional, Feinstein, Sheldon I., additional, Fisher, Aron B., additional, and Chatterjee, Shampa, additional

Published
2014
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171. PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium

Author

Noel, John, primary, Wang, Hui, additional, Hong, Nankang, additional, Tao, Jian-Qin, additional, Yu, Kevin, additional, Sorokina, Elena M., additional, DeBolt, Kristine, additional, Heayn, Michelle, additional, Rizzo, Victor, additional, Delisser, Horace, additional, Fisher, Aron B., additional, and Chatterjee, Shampa, additional

Published
2013
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197. The phospholipase A2activity of peroxiredoxin 6 [S]

Author

Fisher, Aron B.

Abstract

Peroxiredoxin 6 (Prdx6) is a Ca2+-independent intracellular phospholipase A2(called aiPLA2) that is localized to cytosol, lysosomes, and lysosomal-related organelles. Activity is minimal at cytosolic pH but is increased significantly with enzyme phosphorylation, at acidic pH, and in the presence of oxidized phospholipid substrate; maximal activity with phosphorylated aiPLA2is ∼2 µmol/min/mg protein. Prdx6 is a “moonlighting” protein that also expresses glutathione peroxidase and lysophosphatidylcholine acyl transferase activities. The catalytic site for aiPLA2activity is an S32-H26-D140 triad; S32-H26 is also the phospholipid binding site. Activity is inhibited by a serine “protease” inhibitor (diethyl p-nitrophenyl phosphate), an analog of the PLA2transition state [1-hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol (MJ33)], and by two naturally occurring proteins (surfactant protein A and p67phox), but not by bromoenol lactone. aiPLA2activity has important physiological roles in the turnover (synthesis and degradation) of lung surfactant phospholipids, in the repair of peroxidized cell membranes, and in the activation of NADPH oxidase type 2 (NOX2). The enzyme has been implicated in acute lung injury, carcinogenesis, neurodegenerative diseases, diabetes, male infertility, and sundry other conditions, although its specific roles have not been well defined. Protein mutations and animal models are now available to further investigate the roles of Prdx6-aiPLA2activity in normal and pathological physiology.

Published
2018
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