Thioredoxin/Txnip: Redoxisome, as a Redox Switch for the Pathogenesis of Diseases

Abstract

During the past few decades, it has been widely recognized that Reduction-Oxidation (redox) responses occurring at the intra- and extra-cellular levels are one of most important biological phenomena and dysregulated redox responses are involved in the initiation and progression of multiple diseases. Thioredoxin1 (Trx1) and Thioredoxin2 (Trx2), mainly located in the cytoplasm and mitochondria, respectively, are ubiquitously expressed in variety of cells and control cellular reactive oxygen species by reducing the disulfides into thiol groups. Thioredoxin interacting protein (Txnip/thioredoxin binding protein-2/vitamin D3 upregulated protein) directly binds to Trx1 and Trx2 (Trx) and inhibit the reducing activity of Trx through their disulfide exchange. Recent studies have revealed that Trx1 and Txnip are involved in some critical redox-dependent signal pathways including NLRP-3 inflammasome activation in a redox-dependent manner. Therefore, Trx/Txnip, a redox-sensitive signaling complex is a regulator of cellular redox status and has emerged as a key component in the link between redox regulation and the pathogenesis of diseases. Here, we review the novel functional concept of the redox-related protein complex, named “Redoxisome,” consisting of Trx/Txnip, as a critical regulator for intra- and extra-cellular redox signaling, involved in the pathogenesis of various diseases such as cancer, autoimmune disease, and diabetes.

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

“…Several studies have indicated that a disturbance in the redox state of an organism leads to aging and age-related diseases [35–37]. Due to these unique features, Trx, along with thioredoxin interacting protein (Txnip), has been shown to play very important roles in physiology and its dysregulation could be involved in various diseases [38]. However, the roles of Trx on aging and age-related pathology in mammals have not fully been investigated.…”

Effects of muscular dystrophy, exercise and blocking activin receptor IIB ligands on the unfolded protein response and oxidative stress

“…Conversely, TxNIP inhibits the thioredoxin system, which is a key antioxidant system that protects cells from oxidative stress through its disulfide reductase activity [53]. It was previously shown that ER stress increases TxNIP levels through induction of IRE1α activity [39].…”

Diverting Glycolysis to Combat Oxidative Stress

“…Interestingly, the α-arrestin family member Trx-interacting protein (TXNIP) seems to integrate glucose availability and ROS. As its name indicates, TXNIP forms intermolecular disulfi des with Trx, inhibiting it and promoting oxidative stress [ 36 ]. TXNIP furthermore regulates the glucose transporter Glut1 by suppressing Glut1 mRNA and promoting its internalization via clathrin-coated pits.…”