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.

Keywords: Txnip; diabetes mellitus; inflammation; redox regulation; redoxisome; thioredoxin.

Figure 1

Trx/Txnip signaling complex as redoxisome. Txnip contains an intramolecular disulfide band between Cys-63 and -247 that allows efficient interaction with Trx. Txnip forms disulfide bond with reduced TRX by disulfide exchange, making a stable Trx mixed disulfide.

Figure 2

Beneficial effect of Trx1/Txnip signaling for clinical aspect. The beneficial effect by increasing of Trx1 and decreasing of Txnip expression are shown. Green box indicate the beneficial effect in diabetes while red box indicate the concern about adverse effect in cancer development by reduced Txnip expression.