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Review
. 2022 May;36(13-15):1001-1022.
doi: 10.1089/ars.2021.0038. Epub 2021 Oct 7.

Thioredoxin-Interacting Protein in Cancer and Diabetes

Hiroshi Masutani  1   2
Affiliations
Review

Thioredoxin-Interacting Protein in Cancer and Diabetes

Hiroshi Masutani. Antioxid Redox Signal. 2022 May.

Abstract

Significance: 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. Recent Advances: 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. Critical Issues: 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. Future Directions: 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. Antioxid. Redox Signal. 36, 1001-1022.

Keywords: ARRDC3; RNA; TBP-2); autophagy; cancer; thioredoxin; thioredoxin-binding protein-2; thioredoxin-interacting protein (Txnip; α-arrestin.

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Conflict of interest statement

The author has no conflict of interest.

Figures

FIG. 1.
FIG. 1.
Txnip is a regulator of fasting responses, metabolism, and cancer. In the era of hunger, Txnip is a critical survival gene to protect against fasting, and acts as a feedback regulator to utilize glucose within an appropriate range and maintain energy balance (AMP/ATP ratio). In the era of satiety, sustained hyperglycemia, which is not expected in the era of hunger, may cause Txnip to exert unanticipated effects in metabolism. In periods of satiety, sustained hyperglycemia induces augmented Txnip expression, causing suppression of glucose uptake of muscle and adipose tissues and insulin secretion from pancreatic β-cells, leading to an increased risk of diabetes. Here, we are in the era of longevity. The Txnip gene is downregulated mainly by epigenetic mechanisms in cancer cells, resulting in augmented glucose uptake, thus favoring tumor growth. Decreased expression of Txnip also changes the RNA and protein expression pattern to promote tumor growth. Txnip, thioredoxin-interacting protein. Color images are available online.
FIG. 2.
FIG. 2.
Regulation of Txnip expression. Txnip expression is regulated in a multifaceted manner. (A) Transcriptional regulation of the Txnip gene. Txnip expression is regulated by multiple regulatory elements and transcription factors. Among them, glucose response through ChREBP/Mlx or MondoA/Mlx through ChoRE is most important. Myc may exert metabolic regulating effects and tumor promoting function by competitively binding to the ChoRE elements. MicroRNAs also play important regulatory roles of Txnip expression. (B) Epigenetic regulation of the Txnip gene. Txnip is regulated by multiple epigenetic mechanisms, including histone methylation, histone deacetylation, and DNA methylation. UHRF1 recruits HDAC1 and mediated histone deacetylation at H3K9 (66). UHRF1 is reported to ubiquitinate histone H3, recruiting DNMT1 to induce DNA methylation (109). ChoRE, carbohydrate-response element; ChREBP, carbohydrate response element-binding protein; DNMT1, DNA methyltransferase 1; HDAC, histone deacetylase; Mlx, Max-like protein X; RING, really interesting new gene; UHRF1, ubiquitin-like protein containing PHD and RING finger domains 1. Color images are available online.
FIG. 3.
FIG. 3.
Control of Txnip mRNA turnover. Txnip expression is reported at the level of mRNA turnover (144). Hyaluronidase treatment activates receptor tyrosine kinase activation, leading to the induction of ZFP36 expression. ZFP36 binds to the mRNA of Txnip to induce degradation of Txnip mRNA. mRNA, messenger RNA; ZFP36, zinc finger protein 36 homolog. Color images are available online.
FIG. 4.
FIG. 4.
Regulation of Txnip protein expression. Txnip protein is rapidly turned over by the regulation of NEDD family ubiquitin ligases such as ITCH. Txnip is phosphorylated by several kinases, including AMPK and AKT. Glucose inhibits AMPK and subsequently leads to the accumulation of Txnip protein level. Txnip interacts with yet unelucidated binding partners, which seem to change the RNA expression pattern. Txnip is also proposed to interact with binding partners such as GLUT1 and GLUT4 to change their intracellular localization. The precise regulatory mechanisms how Txnip regulates each binding partner and their fate are to be determined. AMPK, AMP-activated protein kinase; GLUT, glucose transporter; ITCH, itchy E3 ubiquitin protein ligase; NEDD, neural precursor cell expressed developmentally down-regulated protein. Color images are available online.
FIG. 5.
FIG. 5.
Features of α-arrestin family proteins. α-Arrestin family proteins have arrestin N and C domains and conserved PPXY motifs. ARRDC5 is a testis-specific paralog and lacks the PPXY motifs. Txnip and ARRDC2 are localized mainly in the nucleus, whereas ARRDC3 is localized to the inner plasma membrane and endosomes. ARRDC1 and ARRDC4 are detected in ARMMs. Downregulation of Txnip is associated with cancer, whereas its upregulation worsens diabetes. Downregulation of ARRDC3 has also been reported in cancer, while its decrease augments energy expenditure to ameliorate obesity. ARMMs, ARRDC1-mediated microvesicles; ARRDC, arrestin domain containing. Color images are available online.
FIG. 6.
FIG. 6.
α-Arrestin family proteins are regulators of intracellular and extracellular traffic. Like their counterparts in the yeast system, α-arrestin family proteins seem to play important roles in intracellular and extracellular traffic. ARRDC3 is a key regulator of endocytosis of receptors, including the β2-adrenergic receptor, together with NEDD family ubiquitin ligases. The role of ARRDC3 in recycling endosomes and lysosomes does not seem to be determined. ARRDC1, ARRDC4, and NEDD family ubiquitin ligases are detected in ARMMs for packaging and the intracellular delivery of macromolecules. Multivesicular body contains vesicles, which are exosomes once the multivesicular body fuses with the plasma membrane. The role of α-arrestin family proteins in multivesicular endosomes and exosomes is not clear. Note that intracellular and extracellular vesicles in this figure are not drawn in the proportion to the actual size. Color images are available online.
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