Thioredoxin and Its Relatives Are Specific Regulators

Abstract

The formation of reactive oxygen species is implicated in many signaling processes, including the pathways triggered by tumor necrosis factor-α (TNF-α). Thioredoxin (Trx) and thioredoxin-related proteins (TRP) are disulfide reductases that contribute to the redox regulation of cells. In their reduced form, these enzymes can reduce disulfide bonds in substrate proteins. In two articles this week, Jeong et al . characterized the activity of TRP14 and compared the roles of TRP14 and Trx1 in TNF-α signaling using overexpression or depletion by RNA interference. Both proteins inhibit nuclear factor-κB (NF-κB) signaling, as determined by increased Mn 2+ -dependent superoxide dismutase expression (an NF-κB target gene), in response to TNF-α exposure in cells depleted of Trx1 or TRP14. The rate and extent of phosphorylation and degradation of the inhibitor of κB (IκBα) were also increased in Trx1- or TRP14-depleted cells. Depletion of Trx1 or TRP14 also resulted in accelerated caspase cleavage and enhanced cell death in TNF-α-stimulated cells in which protein synthesis was blocked. More interesting were the differences observed after depletion of TRP14 and Trx1. Depletion of Trx1 did not affect the time course or extent of phosphorylation of the two mitogen-activated protein kinase (MAPK) family members JNK and p38, whereas depletion of TRP14 did not alter the time course of phosphorylation but did increase the extent of phosphorylation of these two enzymes. Another difference was the interaction and inhibition of the MAPK kinase kinase ASK1 by Trx1, which did not occur with TRP14. In vitro substrate trapping experiments identified LC8 (the light chain of dynein, which is also known to interact with IκBα and the Bcl-2 member Bim), cofilin, and ribosomal protein L30 as potential substrates of TRP14. In transfected cells, LC8 and TRP14 formed a complex in response to TNF-α or peroxide treatment. Thus, the thioredoxin family of proteins appears to serve specific regulatory roles in redox regulation. W. Jeong, T.-S. Chang, E. S. Boja, H. M. Fales, S. G. Rhee, Roles of TRP14, a thioredoxin-related protein in tumor necrosis factor-α signaling pathways. J. Biol. Chem. 279 , 3151-3159 (2004). [Abstract] [Full Text] W. Jeong, H. W. Yoon, S.-R. Lee, S. G. Rhee, Identification and characterization of TRP14, a thioredoxin-related protein of 14 kDa: new insights into the specificity of thioredoxin function. J. Biol. Chem. 279 , 3142-3150 (2004). [Abstract] [Full Text]