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Oxidative Medicine and Cellular... 2022Thioredoxin-interacting protein (TXNIP) was originally named vitamin D upregulated protein-1 (VDUP1) because of its ability to bind to thioredoxin (TRX) and inhibit TRX... (Review)
Review
Thioredoxin-interacting protein (TXNIP) was originally named vitamin D upregulated protein-1 (VDUP1) because of its ability to bind to thioredoxin (TRX) and inhibit TRX function and expression. TXNIP is an alpha-arrestin protein that is essential for redox homeostasis in the human body. TXNIP may act as a double-edged sword in the cell. The balance of TXNIP is crucial. A study has shown that TXNIP can travel between diverse intracellular locations and bind to different proteins to play different roles under oxidative stress. The primary function of TXNIP is to induce apoptosis or pyroptosis under oxidative stress. TXNIP also inhibits proliferation and migration in cancer cells, although TXNIP levels decrease, and function diminishes in various cancers. In this review, we summarized the main structure, binding proteins, pathways, and the role of TXNIP in diseases, aiming to explore the double-edged sword role of TXNIP, and expect it to be helpful for future treatment using TXNIP as a therapeutic target.
Topics: Apoptosis; Carrier Proteins; Humans; Neoplasms; Oxidation-Reduction; Oxidative Stress; Thioredoxins
PubMed: 35450411
DOI: 10.1155/2022/7805115 -
Science Immunology Nov 2022The danger signals that activate the NLRP1 inflammasome have not been established. Here, we report that the oxidized, but not the reduced, form of thioredoxin-1 (TRX1)...
The danger signals that activate the NLRP1 inflammasome have not been established. Here, we report that the oxidized, but not the reduced, form of thioredoxin-1 (TRX1) binds to NLRP1. We found that oxidized TRX1 associates with the NACHT-LRR region of NLRP1 in an ATP-dependent process, forming a stable complex that restrains inflammasome activation. Consistent with these findings, patient-derived and ATPase-inactivating mutations in the NACHT-LRR region that cause hyperactive inflammasome formation interfere with TRX1 binding. Overall, this work strongly suggests that reductive stress, the cellular perturbation that will eliminate oxidized TRX1 and abrogate the TRX1-NLRP1 interaction, is a danger signal that activates the NLRP1 inflammasome.
Topics: Humans; Inflammasomes; Thioredoxins; Adaptor Proteins, Signal Transducing; NLR Proteins
PubMed: 36332009
DOI: 10.1126/sciimmunol.abm7200 -
Journal of Experimental Botany Oct 2023Integration of reactive oxygen species (ROS)-mediated signal transduction pathways via redox sensors and the thiol-dependent signalling network is of increasing interest... (Review)
Review
Integration of reactive oxygen species (ROS)-mediated signal transduction pathways via redox sensors and the thiol-dependent signalling network is of increasing interest in cell biology for their implications in plant growth and productivity. Redox regulation is an important point of control in protein structure, interactions, cellular location, and function, with thioredoxins (TRXs) and glutaredoxins (GRXs) being key players in the maintenance of cellular redox homeostasis. The crosstalk between second messengers, ROS, thiol redox signalling, and redox homeostasis-related genes controls almost every aspect of plant development and stress response. We review the emerging roles of TRXs and GRXs in redox-regulated processes interacting with other cell signalling systems such as organellar retrograde communication and gene expression, especially in plants during their development and under stressful environments. This approach will cast light on the specific role of these proteins as redox signalling components, and their importance in different developmental processes during abiotic stress.
Topics: Thioredoxins; Glutaredoxins; Reactive Oxygen Species; Oxidation-Reduction; Signal Transduction; Sulfhydryl Compounds; Transcription, Genetic
PubMed: 37453076
DOI: 10.1093/jxb/erad270 -
Antioxidants & Redox Signaling May 2022Thioredoxin-interacting protein (Txnip) is an α-arrestin protein that acts as a cancer suppressor. Txnip is simultaneously a critical regulator of energy metabolism.... (Review)
Review
Thioredoxin-interacting protein (Txnip) is an α-arrestin protein that acts as a cancer suppressor. Txnip is simultaneously a critical regulator of energy metabolism. Other alpha-arrestin proteins also play key roles in cell biology and cancer. Txnip expression is regulated by multilayered mechanisms, including transcriptional regulation, microRNA, messenger RNA (mRNA) stabilization, and protein degradation. The Txnip-based connection between cancer and metabolism has been widely recognized. Meanwhile, new aspects are proposed for the mechanism of action of Txnip, including the regulation of RNA expression and autophagy. Arrestin domain containing 3 (ARRDC3), another α-arrestin protein, regulates endocytosis and signaling, whereas ARRDC1 and ARRDC4 regulate extracellular vesicle formation. The mechanism of action of Txnip is yet to be elucidated. The regulation of intracellular protein trafficking by arrestin family proteins has opened an emerging field of biology and medical research, which needs to be examined further. A fundamental understanding of the mechanism of action of Txnip and other arrestin family members needs to be explored in the future to combat diseases such as cancer and diabetes. . 36, 1001-1022.
Topics: Arrestins; Diabetes Mellitus; Humans; Neoplasms; Protein Transport; Thioredoxins
PubMed: 34384271
DOI: 10.1089/ars.2021.0038 -
Biochimica Et Biophysica Acta Apr 2008During the 70s and 80s two plant thioredoxin systems were identified. The chloroplastic system is composed of a ferredoxin-dependent thioredoxin, with two thioredoxin... (Review)
Review
During the 70s and 80s two plant thioredoxin systems were identified. The chloroplastic system is composed of a ferredoxin-dependent thioredoxin, with two thioredoxin types (m and f) regulating the activity of enzymes implicated in photosynthetic carbon assimilation. In the cytosol of heterotrophic tissues, an NADP dependent thioredoxin reductase and a thioredoxin (h) were identified. The first plant glutaredoxin was only identified later, in 1994. Our view of plant thioredoxins and glutaredoxins was profoundly modified by the sequencing programs which revealed an unexpected number of genes encoding not only the previously identified disulfide reductases, but also numerous new types. At the same time it became clear that plant genomes encode chloroplastic, cytosolic and mitochondrial peroxiredoxins, suggesting a major role for redoxins in anti-oxidant defense. Efficient proteomics approaches were developed allowing the characterization of numerous thioredoxin target proteins. They are implicated in different aspects of plant life including development and adaptation to environmental changes and stresses. The most important challenge for the next years will probably be to identify in planta which redoxin reduces which target, a question which remains unsolved due to the low specificities of redoxins in vitro and the numerous redundancies which in most cases mask the phenotype of redoxin mutants.
Topics: Genome, Plant; Glutaredoxins; Oxidation-Reduction; Plant Proteins; Plants; Thioredoxins
PubMed: 18047840
DOI: 10.1016/j.bbamcr.2007.10.017 -
The Journal of Biological Chemistry 2021Environmental sequence data of microbial communities now makes up the majority of public genomic information. The assignment of a function to sequences from these...
Environmental sequence data of microbial communities now makes up the majority of public genomic information. The assignment of a function to sequences from these metagenomic sources is challenging because organisms associated with the data are often uncharacterized and not cultivable. To overcome these challenges, we created a rationally designed expression library of metagenomic proteins covering the sequence space of the thioredoxin superfamily. This library of 100 individual proteins represents more than 22,000 thioredoxins found in the Global Ocean Sampling data set. We screened this library for the functional rescue of Escherichia coli mutants lacking the thioredoxin-type reductase (ΔtrxA), isomerase (ΔdsbC), or oxidase (ΔdsbA). We were able to assign functions to more than a quarter of our representative proteins. The in vivo function of a given representative could not be predicted by phylogenetic relation but did correlate with the predicted isoelectric surface potential of the protein. Selected proteins were then purified, and we determined their activity using a standard insulin reduction assay and measured their redox potential. An unexpected gel shift of protein E5 during the redox potential determination revealed a redox cycle distinct from that of typical thioredoxin-superfamily oxidoreductases. Instead of the intramolecular disulfide bond formation typical for thioredoxins, this protein forms an intermolecular disulfide between the attacking cysteines of two separate subunits during its catalytic cycle. Our functional metagenomic approach proved not only useful to assign in vivo functions to representatives of thousands of proteins but also uncovered a novel reaction mechanism in a seemingly well-known protein superfamily.
Topics: Catalysis; Cysteine; Environmental Monitoring; Escherichia coli; Glutaredoxins; Metagenomics; Multigene Family; Oceans and Seas; Oxidation-Reduction; Phylogeny; Protein Disulfide-Isomerases; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 33361108
DOI: 10.1074/jbc.RA120.016350 -
American Journal of Physiology. Heart... Aug 2021
Topics: Thioredoxins
PubMed: 34170195
DOI: 10.1152/ajpheart.00330.2021 -
Frontiers in Immunology 2022Target identification is essential for developing novel therapeutic strategies in diseases. Thioredoxin-interacting protein (TXNIP), also known as thioredoxin-binding... (Review)
Review
Target identification is essential for developing novel therapeutic strategies in diseases. Thioredoxin-interacting protein (TXNIP), also known as thioredoxin-binding protein-2, is a member of the α-arrestin protein family and is regulated by several cellular stress factors. TXNIP overexpression coupled with thioredoxin inhibits its antioxidant functions, thereby increasing oxidative stress. TXNIP is directly involved in inflammatory activation by interacting with Nod-like receptor protein 3 inflammasome. Bone metabolic disorders are associated with aging, oxidative stress, and inflammation. They are characterized by an imbalance between bone formation involving osteoblasts and bone resorption by osteoclasts, and by chondrocyte destruction. The role of TXNIP in bone metabolic diseases has been extensively investigated. Here, we discuss the roles of TXNIP in the regulatory mechanisms of transcription and protein levels and summarize its involvement in bone metabolic disorders such as osteoporosis, osteoarthritis, and rheumatoid arthritis. TXNIP is expressed in osteoblasts, osteoclasts, and chondrocytes and affects the differentiation and functioning of skeletal cells through both redox-dependent and -independent regulatory mechanisms. Therefore, TXNIP is a potential regulatory and functional factor in bone metabolism and a possible new target for the treatment of bone metabolism-related diseases.
Topics: Bone Diseases, Metabolic; Carrier Proteins; Humans; Inflammasomes; Metabolic Diseases; Thioredoxins
PubMed: 36059548
DOI: 10.3389/fimmu.2022.955128 -
Plant Science : An International... Feb 2019Activation of plant immune responses is associated with rapid production of vast amounts of reactive oxygen and nitrogen species (ROS/RNS) that dramatically alter... (Review)
Review
Activation of plant immune responses is associated with rapid production of vast amounts of reactive oxygen and nitrogen species (ROS/RNS) that dramatically alter cellular redox homeostasis. Even though excessive ROS/RNS accumulation can cause widespread cellular damage and thus constitute a major risk, plant cells have evolved to utilise these molecules as important signalling cues. Particularly their ability to modify redox-sensitive cysteine residues has emerged as a key mechanism to control the activity, conformation, protein-protein interaction and localisation of a growing number of immune signalling proteins. Regulated reversal of cysteine oxidation is dependent on activities of the conserved superfamily of Thioredoxin (TRX) enzymes that function as cysteine reductases. The plant immune system recruits specific TRX enzymes that have the potential to functionally regulate numerous immune signalling proteins. Although our knowledge of different TRX immune targets is now expanding, little remains known about how these enzymes select their substrates, what range of oxidized residues they target, and if they function selectively in different redox-mediated immune signalling pathways. In this review we discuss these questions by examining evidence showing TRX enzymes exhibit novel activities that play important roles in diverse aspects of plant immune signalling.
Topics: Oxidation-Reduction; Plant Immunity; Signal Transduction; Thioredoxins
PubMed: 30709489
DOI: 10.1016/j.plantsci.2018.05.001 -
Biochimica Et Biophysica Acta Apr 2008Thiol-disulfide oxidoreductase systems of bacterial cytoplasm and eukaryotic cytosol favor reducing conditions and protein thiol groups, while bacterial periplasm and... (Review)
Review
Thiol-disulfide oxidoreductase systems of bacterial cytoplasm and eukaryotic cytosol favor reducing conditions and protein thiol groups, while bacterial periplasm and eukaryotic endoplasmatic reticulum provide oxidizing conditions and a machinery for disulfide bond formation in the secretory pathway. Oxidoreductases of the thioredoxin fold superfamily catalyze steps in oxidative protein folding via protein-protein interactions and covalent catalysis to act as chaperones and isomerases of disulfides to generate a native fold. The active site dithiol/disulfide of thioredoxin fold proteins is CXXC where variations of the residues inside the disulfide ring are known to increase the redox potential like in protein disulfide isomerases. In the catalytic mechanism thioredoxin fold proteins bind to target proteins through conserved backbone-backbone hydrogen bonds and induce conformational changes of the target disulfide followed by nucleophilic attack by the N-terminally located low pK(a) Cys residue. This generates a mixed disulfide covalent bond which subsequently is resolved by attack from the C-terminally located Cys residue. This review will focus on two members of the thioredoxin superfamily of proteins known to be crucial for maintaining a reduced intracellular redox state, thioredoxin and glutaredoxin, and their potential functions as facilitators and regulators of protein folding and chaperone activity.
Topics: Glutaredoxins; Molecular Chaperones; Oxidation-Reduction; Protein Folding; Thioredoxins
PubMed: 18331844
DOI: 10.1016/j.bbamcr.2008.02.003