The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor.
Arrestin domain-containing protein 3 (ARRDC3) is a member of the mammalian α-arrestin family, which is predicted to share similar tertiary structure with visual-/β-arrestins and also contains C-terminal PPXY motifs that mediate interaction with E3 ubiquitin ligases. Recently, ARRDC3 has been proposed to play a role in regulating the trafficking of G protein-coupled receptors, although mechanistic insight into this process is lacking. Here, we focused on characterizing the role of ARRDC3 in regulating the trafficking of the β2-adrenergic receptor (β2AR). We find that ARRDC3 primarily localizes to EEA1-positive early endosomes and directly interacts with the β2AR in a ligand-independent manner. Although ARRDC3 has no effect on β2AR endocytosis or degradation, it negatively regulates β2AR entry into SNX27-occupied endosomal tubules. This results in delayed recycling of the receptor and a concomitant increase in β2AR-dependent endosomal signaling. Thus, ARRDC3 functions as a switch to modulate the endosomal residence time and subsequent intracellular signaling of the β2AR.
Tian, Xufan; Irannejad, Roshanak; Bowman, Shanna L.; Du, Yang; Puthenveedu, Manojkumar A.; von Zastrow, Mark; and Benovic, Jeffrey L., "The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor." (2016). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 104.
This research was originally published in Journal of Biological Chemistry. Tian, X., Irannejad, R., Bowman, S.L., Du, Y., Puthenveedu, M.A., Von Zastrow, M., Benovic, J.L. The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor. Journal of Biological Chemistry. July 2016; 291:14510-14525. © The American Society for Biochemistry and Molecular Biology