Publication date: Available online 12 February 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Lucía González-Perilli, Mauricio Mastrogiovanni, Denise de Castro Fernandes, Homero Rubbo, Francisco Laurindo, Andrés Trostchansky
BackgroundNitroarachidonic acid (NO2AA) exhibits pleiotropic anti-inflammatory actions in a variety of cell types. We have recently shown that NO2AA inhibits phagocytic NADPH oxidase 2 (NOX2) by preventing the formation of the active complex. Recent work indicates the participation of protein disulfide isomerase (PDI) activity in NOX2 activation. Cysteine (Cys) residues at PDI active sites could be targets for NO2AA- nitroalkylation regulating PDI activity which could explain our previous observation.MethodsPDI reductase and chaperone activities were assessed using the insulin and GFP renaturation method in the presence or absence of NO2-AA. To determine the covalent reaction with PDI as well as the site of reaction, the PEG-Switch assay and LC-MS/MS studies were performed.Results and ConclusionsWe determined that both activities of PDI were inhibited by NO2AA in a dose- and time- dependent manner and independent from release of nitric oxide. Since nitroalkenes are potent electrophiles and PDI has critical Cys residues for its activity, then formation of a covalent adduct between NO2AA and PDI is feasible. To this end we demonstrated the reversible covalent modification of PDI by NO2AA. Trypsinization of modified PDI confirmed that the Cys residues present in the active site a´ of PDI were key targets accounting for nitroalkene modification.General significancePDI may contribute to NOX2 activation. As such, inhibition of PDI by NO2AA might be involved in preventing NOX2 activation. Future work will be directed to determine if the covalent modifications observed play a role in the reported NO2AA inhibition of NOX2 activity.
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