Significance: The presence of a large number of thioredoxin superfamily members suggests a complex mechanism of redox-based regulation in mammalian cells. However, whether these members are functionally redundant or play separate and distinct roles in each cellular compartment remains to be elucidated. Recent Advances: In the mammalian endoplasmic reticulum (ER), ∼20 thioredoxin-like proteins have been identified. Most ER oxidoreductases are soluble proteins located in the luminal compartment, whereas a small family of five thioredoxin-related transmembrane proteins (TMX) also reside in the ER membrane and play crucial roles with specialized functions. Critical Issues: In addition to the predicted function of ER protein quality control, several independent studies have suggested the diverse roles of TMX family proteins in the regulation of cellular processes, including calcium homeostasis, bioenergetics, and thiol-disulfide exchange in the extracellular space. Moreover, recent studies have provided evidence of their involvement in the pathogenesis of various diseases. Future Directions: Extensive research is required to unravel the physiological roles of TMX family proteins. Given that membrane-associated proteins are prime targets for drug discovery in a variety of human diseases, expanding our knowledge on the mechanistic details of TMX action on the cell membrane will provide the molecular basis for developing novel diagnostic and therapeutic approaches as a potent molecular target in a clinical setting. Antioxid. Redox Signal. 36, 984-1000.
Keywords: TMX; disulfide; endoplasmic reticulum; oxidoreductase; redox; thioredoxin.