Introducing Thioredoxin-Related Transmembrane Proteins: Emerging Roles of Human TMX and Clinical Implications

Abstract

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), approximately 20 thioredoxin-like proteins have been identified. Most ER oxidoreductases are soluble proteins located in the luminal compartment, while a small family of five thioredoxinrelated 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 thioldisulfide 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 molecular basis for developing novel diagnostic and therapeutic approaches as a potent molecular target in a clinical setting.

Elovanoid-N34 is a homeostatic switch that modulates TXNRD1 for cell survival

“…The TMX basal state is reduced, and as ER stress overcomes, the pool become oxidized. Reductases may get into play to restore the pool of active TMX so the ERAD can proceed [21]. The results indicate that TXNRD1 from the membrane and cytosol could be the reductase from the glutathione system [22] that switches the TMX on-off at the different locations, including the ER, connecting its function with protein unfolding with many pathologies, including neurodegenerative diseases.…”

“…Here for the rst time, we uncover that a lipid mediator interacts and exerts a structural con guration modi cation on TXNRD1 that leads to the modulation of its activity. TXNRD1 control pathways of cell viability, ferroptosis, ER stress response, and mitochondria renewal, among other changes, are triggered by redox states [20,21]. TXNRD1 is coupled to TRX in the TXN complex.…”

Anterior gradient proteins in gastrointestinal cancers: from cell biology to pathophysiology

“…Along with glutaredoxins and thioredoxins, PDI are members of the thioredoxin (TRX) superfamily which are characterized by the presence of a thioredoxin fold (5). So far, 20 PDIs have been identified (4,6). Most of them are located in the lumen of the ER, while others are transmembrane proteins (TMX 1 to TMX 5) (6).…”

“…So far, 20 PDIs have been identified (4,6). Most of them are located in the lumen of the ER, while others are transmembrane proteins (TMX 1 to TMX 5) (6). PDI are defined as "proteins that can react with cysteine side chains", but it includes also "proteins that contain non-thiol-reactive thioredoxin-like domains with chaperone-like activities for ER folding and secretion of proteins" (7).…”

SEC62 and TMX4 control asymmetric autophagy of the nuclear envelope upon LINC complex disassembly

“…The proline residue at position 2 destabilizes the disulfide state and favors the di-thiol reduced form of the active site 35 . Consistently, TMX4 acts as reductase in vitro 36 , but its biological function remains to be established 37,38 . The peculiar sub-cellular distribution of TMX4 in the NE, and its reported in vitro activity as a reductase, led us to check if TMX4 interacts with NESPRIN3 and regulates the redox-driven disassembly of LINC complexes.…”