Thioredoxin and Thioredoxin Target Proteins: From Molecular Mechanisms to Functional Significance

Abstract

The thioredoxin (Trx) system is one of the central antioxidant systems in mammalian cells, maintaining a reducing environment by catalyzing electron flux from nicotinamide adenine dinucleotide phosphate through Trx reductase to Trx, which reduces its target proteins using highly conserved thiol groups. While the importance of protecting cells from the detrimental effects of reactive oxygen species is clear, decades of research in this field revealed that there is a network of redox-sensitive proteins forming redox-dependent signaling pathways that are crucial for fundamental cellular processes, including metabolism, proliferation, differentiation, migration, and apoptosis. Trx participates in signaling pathways interacting with different proteins to control their dynamic regulation of structure and function. In this review, we focus on Trx target proteins that are involved in redox-dependent signaling pathways. Specifically, Trx-dependent reductive enzymes that participate in classical redox reactions and redox-sensitive signaling molecules are discussed in greater detail. The latter are extensively discussed, as ongoing research unveils more and more details about the complex signaling networks of Trx-sensitive signaling molecules such as apoptosis signal-regulating kinase 1, Trx interacting protein, and phosphatase and tensin homolog, thus highlighting the potential direct and indirect impact of their redox-dependent interaction with Trx. Overall, the findings that are described here illustrate the importance and complexity of Trx-dependent, redox-sensitive signaling in the cell. Our increasing understanding of the components and mechanisms of these signaling pathways could lead to the identification of new potential targets for the treatment of diseases, including cancer and diabetes.

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

“…One possible explanation is that loss of the ability to reduce thioredoxin may have a broad impact on all thioredoxin-dependent targets, including mitochondrial perioxiredoxins other than PRX3, or Trx-dependent protein complexes that might impact ROS production or scavenging indirectly (34). Second, increased oxidative stress upon TXNRD2 knockdown could be further enhanced by hyperoxidation of PRX3, which is known to occur after treatment with auranofin, a thioredoxin reductase inhibitor, or other stressors (35)(36)(37)(38).…”

Novel function of PITH domain-containing 1 as an activator of internal ribosomal entry site to enhance RUNX1 expression and promote megakaryocyte differentiation

“…By altering their redox state, TRX regulates the functions of at least 30 target proteins. It also plays an important role in the defense against oxidative stress [22]. To address whether PITHD1 function as a potential thioredoxin, we measured ROS product in PITHD1 overexpressing K562 cells.…”

Comparative selenoproteome analysis reveals a reduced utilization of selenium in parasitic platyhelminthes

“…Selenophosphate synthetase 2 (SPS2) is an essential component of Sec biosynthesis (Turanov et al 2011). Thioredoxin reductases (TR) are a group of enzymes known to catalyze the reduction of thioredoxin and hence are central components in the thioredoxin system (Lee et al 2013). The 15kD selenoprotein (Sel15) has redox function and may be involved in the quality control of protein folding (Kasaikina et al 2011).…”