Redox Receptor Regulation Revealed

Abstract

Thioredoxin-1 (Trx1) is a thiol-disulfide oxidoreductase that can reduce transiently formed disulfide bonds in substrate proteins. The enzyme is released from lymphocytes and has extracellular cytokine-like actions, but the mechanisms by which it produces such effects are not known. Schwertassek et al . used a modified form of Trx1 in a substrate trapping assay (in which the engineered Trx1 formed long-lived mixed disulfide intermediates with its targets) to search for cell-surface proteins that might be modified by the enzyme. An affinity tag on the modified Trx1 allowed purification of the complexes and subsequent identification of associated proteins by mass spectrometry. In the human Epstein-Barr virus--transformed lymphoblastoid B cell line LCL-721.220--the authors found just one primary target of Trx-1, a member of the tumor necrosis factor receptor (TNFR) superfamily known as TNFRSF8 or CD30. The association of the proteins was lost under reducing conditions and, although all TNFR superfamily members characteristically have cysteine-rich domains, association with Trx1 was specific to CD30. Modification of CD30 appeared to cause a conformational change in the receptor because recognition of the receptor by antibodies was altered. This action of Trx1 required the presence of a source of reducing equivalents. Incubation of Hodgkin’s lymphoma HDLM-2 cells decreased binding of recombinant soluble CD30 ligand to its receptor at the cell surface and, in the YT granular lymphoma cell line, blocked increased expression of the gene encoding the interleukin-2 receptor alpha chain, which is normally activated by CD30 signaling. The authors thus propose that excreted Trx1 may alter receptor function and may, in this way, link oxidative stress to lymphocyte function. U. Schwertassek, Y. Balmer, M. Gutscher, L. Weingarten, M. Preuss, J. Engelhard, M. Winkler, T. P. Dick, Selective redox regulation of cytokine receptor signaling by extracellular thioredoxin-1. EMBO J. 26 , 3086-3097 (2007). [PubMed]