A 29-kDa Protein Associated with p67 Expresses Both Peroxiredoxin and Phospholipase A2 Activity and Enhances Superoxide Anion Production by a Cell-free System of NADPH Oxidase Activity

Leavey, Patrick J.; Gonzalez-Aller, Carolina; Thurman, Gail; Kleinberg, Michael; Rinckel, Lori A.; Ambruso, Daniel W.; Freeman, Stefanie H.; Kuypers, Frans A.; Ambruso, Daniel R.

doi:10.1074/jbc.m202869200

Cited by 44 publications

(37 citation statements)

References 37 publications

(53 reference statements)

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“…A similar Prdx6 requirement was demonstrated for agonist-mediated ROS production by alveolar macrophages. A similar conclusion regarding a role for Prdx6 in NOX2 activation was reached in a previous in vitro study of PMN in which ROS production was approximately doubled by the presence of recombinant Prdx6 (also known as p29); this latter study used a reconstituted system consisting of isolated plasma membrane from PMN and recombinant cytosolic proteins (7). Although the recombinant Prdx6 (p29) exhibited both PLA 2 FIGURE 8.…”

Section: Discussionmentioning

confidence: 70%

“…The PLA 2 activity catalyzes the hydrolysis of the acyl group at the sn-2 position of glycerophospholipids, with special affinity for phosphatidylcholine, to produce free fatty acids and a lysophospholipid; the peroxidase activity uses glutathione as the co-factor for reduction of hydroperoxides, including phospholipid hydroperoxides (6). In a previous study, Prdx6 (therein called p29) was found to participate in the activation of NOX2 in human neutrophils (7). However, the mechanism by which Prdx6 might activate NOX2-mediated ROS generation was not determined.…”

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confidence: 99%

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Peroxiredoxin 6 Phosphorylation and Subsequent Phospholipase A2 Activity Are Required for Agonist-mediated Activation of NADPH Oxidase in Mouse Pulmonary Microvascular Endothelium and Alveolar Macrophages

Chatterjee

Feinstein

Dodia

et al. 2011

Journal of Biological Chemistry

125

198

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Peroxiredoxin 6 (Prdx6), a bifunctional enzyme with glutathione peroxidase and phospholipase A2 (PLA 2 ) activities, participates in the activation of NADPH oxidase 2 (NOX2) in neutrophils, but the mechanism for this effect is not known. We now demonstrate that Prdx6 is required for agonist-induced NOX2 activation in pulmonary microvascular endothelial cells (PMVEC) and that the effect requires the PLA 2 activity of Prdx6. Generation of reactive oxygen species (ROS) in response to angiotensin II (Ang II) or phorbol 12-myristate 13-acetate was markedly reduced in perfused lungs and isolated PMVEC from Prdx6 null mice. Rac1 and p47phox , cytosolic components of NOX2, translocated to the endothelial cell membrane after Ang II treatment in wild-type but not Prdx6 null PMVEC. MJ33, an inhibitor of Prdx6 PLA 2 activity, blocked agonist-induced PLA 2 activity and ROS generation in PMVEC by >80%, whereas inhibitors of other PLA 2 s were ineffective. Transfection of Prx6 null cells with wild-type and C47S mutant Prdx6, but not with mutants of the PLA 2 active site (S32A, H26A, and D140A), "rescued" Ang II-induced PLA 2 activity and ROS generation. Ang II treatment of wild-type cells resulted in phosphorylation of Prdx6 and its subsequent translocation from the cytosol to the cell membrane. Phosphorylation as well as PLA 2 activity and ROS generation were markedly reduced by the MAPK inhibitor, U0126. Thus, agonist-induced MAPK activation leads to Prdx6 phosphorylation and translocation to the cell membrane, where its PLA 2 activity facilitates assembly of the NOX2 complex and activation of the oxidase.

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Section: Discussionmentioning

confidence: 70%

mentioning

confidence: 99%

Peroxiredoxin 6 Phosphorylation and Subsequent Phospholipase A2 Activity Are Required for Agonist-mediated Activation of NADPH Oxidase in Mouse Pulmonary Microvascular Endothelium and Alveolar Macrophages

Chatterjee

Feinstein

Dodia

et al. 2011

Journal of Biological Chemistry

125

198

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“…The enzymatic kinetics observed for the removal of H 2 O 2 is comparable to that of peroxiredoxins from P. falciparum, C. elegans, human neutrophils, and Pisum sativum, where similar peroxidase assays were used (Fig. 1D) (8,26,27,32).…”

Section: Resultsmentioning

confidence: 85%

Expression of a Mitochondrial Peroxiredoxin Prevents Programmed Cell Death inLeishmania donovani

Harder

Bente

Isermann³

et al. 2006

Eukaryot Cell

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Leishmania promastigote cells transmitted by the insect vector get phagocytosed by macrophages and convert into the amastigote form. During development and transformation, the parasites are exposed to various concentrations of reactive oxygen species, which can induce programmed cell death (PCD). We show that a mitochondrial peroxiredoxin (LdmPrx) protects Leishmania donovani from PCD. Whereas this peroxiredoxin is restricted to the kinetoplast area in promastigotes, it covers the entire mitochondrion in amastigotes, accompanied by dramatically increased expression. A similar change in the expression pattern was observed during the growth of Leishmania from the early to the late logarithmic phase. Recombinant LdmPrx shows typical peroxiredoxin-like enzyme activity. It is able to detoxify organic and inorganic peroxides and prevents DNA from hydroxyl radical-induced damage. Most notably, Leishmania parasites overexpressing this peroxiredoxin are protected from hydrogen peroxide-induced PCD. This protection is also seen in promastigotes grown to the late logarithmic phase, also characterized by high expression of this peroxiredoxin. Apparently, the physiological role of this peroxiredoxin is stabilization of the mitochondrial membrane potential and, as a consequence, inhibition of PCD through removal of peroxides.Leishmania parasites affect more than 12 million people worldwide, with an estimated 2 million new cases each year (WHO World Health Report, 2004, http://www.who.int/whr /en). Depending on the species involved, symptoms range from the self-healing cutaneous form (Leishmania major) to the fatal visceral form (L. donovani). The parasite is transmitted as the infective promastigote form from the gut of its insect vector, female phlebotomine flies of the genera Phlebotomus and Lutzomyia, to mammalian hosts. Promastigotes get phagocytosed by macrophages and convert into the amastigote form, which is able to survive and replicate within phagolysosomes. During phagocytosis of Leishmania promastigotes, the macrophages produce different reactive oxygen species (ROS) to kill the parasites. ROS readily react with proteins, DNA, and lipids and have been implicated in a wide variety of cell functions, such as signal transduction, redox homeostasis, apoptosis, aging, tumor progression, and pathogen infection (9,19,42,58). Numerous reports have shown that Leishmania parasites are susceptible to ROS-and RNS (reactive nitrogen species)-mediated toxicity (41, 57). In order to survive and establish an infection, they have to cope with these pro-oxidants. In Trypanosomatidae, it was shown that peroxiredoxins are the major antioxidant enzymes that can use different ROS and RNS like H 2 O 2 , hydroperoxides, and ONOO as substrates (56). Peroxiredoxins are found in a great variety of organisms, where they fulfill distinct functions, such as detoxification, signaling, or differentiation (25). In different members of the family Trypanosomatidae, cytosolic, as well as mitochondrial, peroxiredoxins were found (6,10,11,21). Peroxire...

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“…As described above, this lysosomal-type activity in the lung is inhibited by MJ33 (3, 17). PLA 2 activity that is Ca 2ϩ -independent, maximal at pH 4, and inhibited by MJ33 has been demonstrated for Prdx6 isolated from lungs (25,29) and polymorphonuclear leukocytes (46) and for recombinant Prdx6 (12,25). Prdx6 mRNA and protein are widely distributed throughout mammalian tissues, but content in the lung is greater than in other major organs (25,47).…”

Section: Fig 4 Degradation Of [ 3 Hmentioning

confidence: 99%

Altered lung phospholipid metabolism in mice with targeted deletion of lysosomal-type phospholipase A2

Fisher

Dodia

Feinstein

et al. 2005

Journal of Lipid Research

107

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A 29-kDa Protein Associated with p67 Expresses Both Peroxiredoxin and Phospholipase A2 Activity and Enhances Superoxide Anion Production by a Cell-free System of NADPH Oxidase Activity

Abstract: Production of toxic oxygen metabolites provides a mechanism for microbicidal activity of the neutrophil. The NADPH oxidase enzyme system initiates the production of oxygen metabolites by reducing oxygen to form superoxide anion (O 2 .

Cited by 44 publications

References 37 publications

Peroxiredoxin 6 Phosphorylation and Subsequent Phospholipase A2 Activity Are Required for Agonist-mediated Activation of NADPH Oxidase in Mouse Pulmonary Microvascular Endothelium and Alveolar Macrophages

Peroxiredoxin 6 Phosphorylation and Subsequent Phospholipase A2 Activity Are Required for Agonist-mediated Activation of NADPH Oxidase in Mouse Pulmonary Microvascular Endothelium and Alveolar Macrophages

Expression of a Mitochondrial Peroxiredoxin Prevents Programmed Cell Death inLeishmania donovani

Altered lung phospholipid metabolism in mice with targeted deletion of lysosomal-type phospholipase A2

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