Physiological and Pathophysiological Roles of Thioredoxin Interacting Protein: A Perspective on Redox Inflammation and Metabolism

Abstract

Significance: Thioredoxin interacting protein (TXNIP) is a member of the arrestin fold superfamily with important cellular functions, including cellular transport, mitochondrial energy generation, and protein cycling. It is the only arrestin-domain protein known to covalently bind to thioredoxin and plays roles in glucose metabolism, inflammation, apoptosis, and cancer. Recent Advances: The crystal structure of the TXNIP-thioredoxin complex provided details about this fascinating interaction. Recent studies showed that TXNIP is induced by endoplasmic reticulum (ER) stress, activates NLR family pyrin domain containing 3 (NLRP3) inflammasomes, and can regulate glucose transport into cells. The tumor suppressor role of TXNIP in various cancer types and the role of TXNIP in fructose absorption are now described. Critical Issues: The influence of TXNIP on redox state is more complex than its interaction with thioredoxin. Future Directions: It is incompletely understood which functions of TXNIP are thioredoxin-dependent. It is also unclear whether TXNIP binding can inhibit glucose transporters without endocytosis. TXNIP-regulated control of ER stress should also be investigated further. Antioxid. Redox Signal. 38, 442-460.

Keywords: TXNIP; arrestin; glucose; inflammasome; redox state; thioredoxin.

FIG. 1.

TXNIP as a member of the arrestin fold superfamily. (A) TXNIP is a member of the diverse arrestin fold superfamily that is composed of alpha (on top) and beta-arrestin (on bottom) branches. (B) The key cysteine in TXNIP (C247) for binding thioredoxin evolved in animals. Mammals bear a C247 cysteine residue, whereas nonmammalians such as fish and frogs do not (light gray: nonmammalians that do not have TXNIP C247 residue, dark gray: mammalians that have TXNIP C247 residue). TXNIP, thioredoxin interacting protein. (Drawn using iTOL, Letunic et al, 2019 Nuc. Acid. Res, PhytoL and NCBI COBALT, Created using Biorender.com)

FIG. 2.

The TXNIP-thioredoxin interaction. Crystal structure of the TXNIP dimer-thioredoxin complex, resolution 2.7 Å, balls refer to bonding cysteine residues, green and pink are beta sheets and disoriented regions of TXNIP, and yellow and cyan are alpha helices and beta sheets of thioredoxin. Created using PyMOL Molecular Graphics System.

FIG. 3.

A TXNIP autoregulatory pathway of cellular glucose. Autoregulatory pathway of cellular glucose. (A) Glucose metabolites induce Txnip transcription via ChREBP/Mlx or MondoA/Mlx. TXNIP protein binds to GLUT1 on the plasma membrane and facilitates GLUT1 endocytosis via the clarthin pathway. (B) Activated AMPK from energy stress or activated Akt from growth factor stimulation phosphorylates TXNIP on Ser308, leading to its dissociation from GLUT1. This results in the immediate inhibition of GLUT1 endocytosis and acute increase in glucose uptake. AMPK, AMP-activated protein kinase; ChREBP, carbohydrate response element binding protein; GLUT1, glucose transporter 1.

FIG. 4.

Enzymes that generate NADPH at different locations in cell. ALDH1L1/2, aldehyde dehydrogenase 1 family member L1/2; G6PD, glucose-6-phosphate dehydrogenase; H6PD, hexose-6-phosphate dehydrogenase/glucose 1-dehydrogenase; IDH1/2, isocitrate dehydrogenase [NADP(+)]; ME1/3, malic enzyme 1/3; MTHFD1/1L, methylenetetrahydrofolate dehydrogenase cyclohydrolase and formyltetrahydrofolate synthetase 1; NADPH, nicotinamide adenine dinucleotide phosphate; NNT, nicotinamide nucleotide transhydrogenase; PGD, phosphogluconate dehydrogenase.

FIG. 5.

Potential mechanisms by which TXNIP can affect cellular redox state. Visual representation of our current knowledge regarding the potential ways in which TXNIP affects cellular redox state. TXNIP and glucose form an auto-feedback loop together, regulating each other. Glucose is needed to produce NADPH such as via the pentose phosphate pathway. Too much glucose can lead to increased ROS production by the mitochondria in two ways: (1) Increased metabolic flux through mitochondria increases ROS production; (2) excess glucose rigidifies mitochondrial membranes, leading to less efficient OXOPHOS flux and increased ROS. NADPH is consumed by intrinsic cellular defense mechanisms to counter ROS. NADPH is also consumed when oxidized Txn is regenerated. ROS, reactive oxygen species; Txn, thioredoxin.

FIG. 6.

TXNIP participates in diverse processes. TXNIP has reported roles in many pathophysiologic processes. (Created in BioRender.com)