Adiporedoxin, an upstream modulator of endoplasmic reticulum oxidative folding and protein secretion
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Our laboratory identified Adiporedoxin (Adrx), an endoplasmic reticulum localized oxidoreductase whose expression in adipose tissue is many fold greater than other tissues. In gain and loss of function experiments in cultured adipocytes Adrx knock down decreased the secretion of numerous adipokines, extracellular matrix, and transmembrane proteins and over expression increased secretion. Together, these results suggest Adrx regulates an early step in protein secretion from the ER. Immunofluorescence and proteolytic protection assays demonstrated that Adrx is located in the ER membrane with an ER luminal active site. We demonstrated that Adrx regulated protein secretion by affecting the oxidation state of ER redox chaperones. Using a cysteine-modifying PEGylation reagent, we showed Adrx oscillated between a reduced and oxidized form through the -CxxC- active site residues in response to the redox environment of the ER. Consequently, knocking down Adrx impaired the re-oxidation of protein disulfide isomerase, indicating an overlapping function with known regulators of ER redox homeostasis, namely endoplasmic reticulum oxidoreductase 1, and peroxiredoxin 4. Adrx is oxidized within the ER after treatment with hydrogen peroxide (H2O2) and can reduce H2O2 in vitro, suggesting it also acts as an antioxidant. The overexpression of Adrx in adipocytes protected the ER from oxidative stress and rescued adipokine secretion. Pancreatic islets are also highly secretory Adrx is expressed in isolated murine islets. In cultured islet cells, Adrx expression also decreased oxidative stress and correlated with the secretion of insulin, the main regulator of glucose homeostasis. In summary, Adrx expression controls secreted proteins and here we describe its ability to regulate the formation and release of disulfide-bonded proteins by reoxidizing ER chaperones and alleviating oxidative stress. Secreted proteins affect many aspects of metabolism including the control of appetite, glucose homeostasis, inflammation, and adipose tissue fibrosis. Overall, these data suggest that by mediating secreted proteins Adrx functions as important regulator of overall metabolism.