Arrdc4, or arrestin domain-containing protein 4, is a member of the α-arrestin protein family. It has diverse functions including involvement in extracellular vesicle biogenesis, regulation of nutrient transporter trafficking, and participation in innate immune responses [1,2,4,5]. It may be associated with pathways related to glucose metabolism, G-protein-coupled receptors, and the innate immune signaling pathway [1,5]. Genetic models, especially knockout mouse models, have been crucial in uncovering its in-vivo functions.

In gene knockout studies, Arrdc4-KO mice exhibit mild fasting hypoglycemia. Arrdc4 binds to GLUT1, induces its endocytosis, and blocks cellular glucose uptake in cardiomyocytes. Deletion of Arrdc4 improves energy homeostasis during ischemia, protects cardiomyocytes against myocardial infarction, and enhances exercise capacity in diabetes by augmenting tissue glucose transport and mitochondrial respiration [1,3]. In sperm maturation, Arrdc4-mediated extracellular vesicle biogenesis is required as sperm from Arrdc4-/-mice have reduced motility and fertilization capabilities [2].

In conclusion, Arrdc4 plays essential roles in cardiac metabolism, sperm maturation, and the innate immune response. The use of Arrdc4-KO mouse models has provided valuable insights into its functions in ischemic heart disease and diabetes, highlighting its potential as a therapeutic target for these diseases [1,2,3,5].

References:

1. Nakayama, Yoshinobu, Mukai, Nobuhiro, Kreitzer, Geri, Patwari, Parth, Yoshioka, Jun. 2022. Interaction of ARRDC4 With GLUT1 Mediates Metabolic Stress in the Ischemic Heart. In Circulation research, 131, 510-527. doi:10.1161/CIRCRESAHA.122.321351. https://pubmed.ncbi.nlm.nih.gov/35950500/

2. Foot, Natalie J, Gonzalez, Macarena B, Gembus, Kelly, Robker, Rebecca L, Kumar, Sharad. 2021. Arrdc4-dependent extracellular vesicle biogenesis is required for sperm maturation. In Journal of extracellular vesicles, 10, e12113. doi:10.1002/jev2.12113. https://pubmed.ncbi.nlm.nih.gov/34188787/

3. Nakayama, Yoshinobu, Kobayashi, Satoru, Masihuddin, Aliya, Liang, Qiangrong, Yoshioka, Jun. 2024. Systemic Deletion of ARRDC4 Improves Cardiac Reserve and Exercise Capacity in Diabetes. In Circulation research, 135, 416-433. doi:10.1161/CIRCRESAHA.123.323158. https://pubmed.ncbi.nlm.nih.gov/38946541/

4. Farooq, Ammara Usman, Gembus, Kelly, Sandow, Jarrod J, Foot, Natalie J, Kumar, Sharad. . K-29 linked ubiquitination of Arrdc4 regulates its function in extracellular vesicle biogenesis. In Journal of extracellular vesicles, 11, e12188. doi:10.1002/jev2.12188. https://pubmed.ncbi.nlm.nih.gov/35106941/

5. Meng, Jun, Yao, Zhenyu, He, Yaqing, Wu, Tangchun, Cheng, Jinquan. 2017. ARRDC4 regulates enterovirus 71-induced innate immune response by promoting K63 polyubiquitination of MDA5 through TRIM65. In Cell death & disease, 8, e2866. doi:10.1038/cddis.2017.257. https://pubmed.ncbi.nlm.nih.gov/28594402/