Selective redox regulation of cytokine receptor signaling by extracellular thioredoxin-1.
The thiol-disulfide oxidoreductase thioredoxin-1 (Trx1) is known to be secreted by leukocytes and to exhibit cytokine-like properties. Extracellular effects of Trx1 require a functional active site, suggesting a redox-based mechanism of action. However, specific cell surface proteins and pathways coupling extracellular Trx1 redox activity to cellular responses have not been identified so far. Using a mechanism-based kinetic trapping technique to identify disulfide exchange interactions on the intact surface of living lymphocytes, we found that Trx1 catalytically interacts with a single principal target protein. This target protein was identified as the tumor necrosis factor receptor superfamily member 8 (TNFRSF8/CD30). We demonstrate that the redox interaction is highly specific for both Trx1 and CD30 and that the redox state of CD30 determines its ability to engage the cognate ligand and transduce signals. Furthermore, we confirm that Trx1 affects CD30-dependent changes in lymphocyte effector function. Thus, we conclude that receptor-ligand signaling interactions can be selectively regulated by an extracellular redox catalyst.
Schwertassek
Ulla
U
Redox Regulation Research Group, German Cancer Research Center (DKFZ/A160), Heidelberg, Germany.
Balmer
Yves
Y
Gutscher
Marcus
M
Weingarten
Lars
L
Preuss
Marc
M
Engelhard
Johanna
J
Winkler
Monique
M
Dick
Tobias P
TP
D000906:Antibodies / Q000276:immunology; D002384:Catalysis; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D006801:Humans; D017730:Ki-1 Antigen / Q000819:agonists / Q000145:classification / Q000276:immunology / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008214:Lymphocytes / Q000378:metabolism; D010084:Oxidation-Reduction; D011485:Protein Binding; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
D000906:Antibodies; D004220:Disulfides; D000939:Epitopes; D017730:Ki-1 Antigen; D008024:Ligands; C491203:TXN protein, human; D013879:Thioredoxins