Arrestin domain-containing protein 4 (ARRDC4)

Arrestin domain-containing protein 4 (ARRDC4) is an alpha-arrestin family adaptor protein found primarily in endosomes and plasma membranes. It regulates nutrient transporter trafficking—most notably, facilitating endocytosis of glucose transporter 1 (GLUT1)—and suppresses cellular glucose uptake, especially under conditions of metabolic stress such as myocardial ischemia. In the heart, upregulation of ARRDC4 increases ER stress and cardiomyocyte death by blocking glucose entry, while knockout models show enhanced glucose uptake and better survival following ischemic injury. ARRDC4 is also ubiquitinated, particularly at a conserved K270 lysine with K-29-linked ubiquitin chains, which is crucial for its role in extracellular vesicle biogenesis and protein trafficking. Additional functions include regulation of interferon-beta production and acting as a ubiquitin-like ligase-substrate adaptor, connecting it to immune and metabolic responses. ARRDC4 represents an emerging therapeutic target for metabolic and cardiovascular disease but currently lacks approved drug modulators and validated clinical biomarkers[1][2][3][4].

Other names

ARRDC4FLJ36045arrestin domain-containing protein 4

Drugs targeting ARRDC4 would likely act by modulating its scaffold/adaptor function, thus affecting GLUT1 endocytosis, glucose uptake, or protein trafficking. Potential inhibitor molecules could preserve GLUT1 surface expression and enhance glucose uptake during ischemia.