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.