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Peroxiredoxin 6 targeting to lysosomal organelles requires MAPK activity and binding to a chaperone protein 14‐3‐3 epsilon in lung epithelial cells

Peroxiredoxin 6 (Prdx6), a bifunctional protein with both GSH peroxidase and phospholipase A2 (aiPLA2) activities, has been localized to cytosolic and acidic compartments (lamellar bodies and lysosomes) in lung alveolar epithelium. We propose that Prdx6 targeting to lysosomal organelles favors its PLA2 activity which requires an acidic pH. We now show that ERK and p38 MAPK regulate Prdx6 targeting to lysosomal organelles in MLE12 and A549 lung epithelial cell lines. Co‐localization of Prdx6 with lysosomal marker LAMP1 showed a decrease of Prdx6 lysosomal targeting in cells treated with ERK or p38 MAPK inhibitors, or an inhibitor of PKC, an upstream kinase activator of MAPKs. Immunocytochemistry, immunoprecipitation followed by PAGE, and an in situ proximity ligation assay (Duolink) showed interaction between Prdx6 and 14‐3‐3ε, a member of the 14‐3‐3 chaperone system which is known to facilitate transport of signaling proteins in the early secretory pathway. Moreover, inhibition of PKC, ERK or p38 abolished the interaction between Prdx6 and 14‐3‐3ε. This interaction is required for Prdx6 translocation along the exocytotic pathway resulting in its sub‐cellular localization to acidic organelles and consequent activation as a PLA2. These findings suggest that ERK and p38 MAPK regulate Prdx6 targeting to lysosomal organelles by activation of 14‐3‐3ε, as a chaperone protein. [HL019737]