TXNIP/TBP-2: A Master Regulator for Glucose Homeostasis

Abstract

Identification of thioredoxin binding protein-2 (TBP-2), which is currently known as thioredoxin interacting protein (TXNIP), as an important binding partner for thioredoxin (TRX) revealed that an evolutionarily conserved reduction-oxidation (redox) signal complex plays an important role for pathophysiology. Due to the reducing activity of TRX, the TRX/TXNIP signal complex has been shown to be an important regulator for redox-related signal transduction in many types of cells in various species. In addition to its role in redox-dependent regulation, TXNIP has cellular functions that are performed in a redox-independent manner, which largely rely on their scaffolding function as an ancestral α-Arrestin family. Both the redox-dependent and -independent TXNIP functions serve as regulatory pathways in glucose metabolism. This review highlights the key advances in understanding TXNIP function as a master regulator for whole-body glucose homeostasis. The potential for therapeutic advantages of targeting TXNIP in diabetes and the future direction of the study are also discussed.

Keywords: TBP-2; TXNIP; glucose homeostasis.

Figure 1

TXNIP regulates glucose homeostasis as signal complex. The TRX/TXNIP signal complex, redoxisome, is the basis of TXNIP regulation of the reduction–oxidation (redox) response. TXNIP has been known to bind NOD-like receptor protein 3 (NLRP3) and activate the inflammasome. TXNIP is a member of the ancestral α-Arrestin family and TXNIP binds to the Itchy E3 Ubiquitin Protein Ligase (ITCH) and facilitates the ubiquitination of the substrates. TXNIP is transcriptionally regulated by nuclear receptors (NRs) such as peroxisome-proliferator activated receptors (PPARs), glucocorticoid receptor (GR), vitamin D receptor (VDR), and farnesoid X receptor (FXR) in a cell type specific manner. These signal complex/transducers are involved in the physiological functions of TXNIP, including the regulation of glucose homeostasis.

Figure 2

Transcriptional and post-translational modification and protein interacting domains of TXNIP. TXNIP gene expression is regulated by various stimuli. Post-translational modifications and protein interactions of TXNIP influence its protein stability, localization and function in a cellular and context-dependent manner. Protein scaffolding and the biological function of TXNIP are biased in the C-arrestin domain. Two PPxY motifs (PPCY and PPTY) of Txnip bind to the four WW domains of E3 ubiquitin ligase, ITCH. Insulin and AMPK facilitate the protein degradation by serine 308 (S308) phosphorylation of TXNIP. TXNIP forms disulfide bonds with reduced TRX by disulfide exchange through its cysteine 247 (C247). Glucocorticoid–glucocorticoid responsive element (GR–GRE), heat shock factor 1–heat shock element (HSF1–HSE), peroxisome proliferator-activated receptor γ/retinoid X receptor α–peroxisome proliferator-activated receptor element (PPARγ/RXRα–PPRE), MLX interacting protein/Max-like protein X (MondoA/Mlx – ChoRE) or carbohydrate-responsive element-binding protein/Max-like protein X–carbohydrate response element (ChREBP/Mlx-ChoRE), nuclear transcription factor Y subunit α–CCAAT motif (NF-YA–ATTGG/CCAAT), Forkhead Box O1 (FOXO1)–putative FOXO1 binding site (FOXO).

Figure 3

Beneficial effects of TXNIP inhibition for glucose homeostasis. Known effects of TXNIP down-regulation in glucose homeostasis are shown. TXNIP is known to be up-regulated in many tissues of a variety of pathogenic conditions, including T1D and T2D. Broadly, TXNIP down-regulation enhances TRX reducing activity and protects from oxidative stress. TXNIP down-regulation also enhances insulin sensitivity and suppresses inflammation. Tissue specific TXNIP down-regulation may provide safer treatment for T1D and T2D (yellow), and since TXNIP has anti-oncogenic functions in several tissues, chronic whole-body TXNIP inhibition may cause serious issues for cancer development (pink).