title: The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor.
abstract: 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.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Xufan
authors.initials: X
authors.lastname: Tian
authors.affiliation: the Department of Psychiatry, University of California at San Francisco, San Francisco, California 94158.
authors.forename: Roshanak
authors.initials: R
authors.lastname: Irannejad
authors.affiliation: the Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, and.
authors.forename: Shanna L
authors.initials: SL
authors.lastname: Bowman
authors.affiliation: the Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305.
authors.forename: Yang
authors.initials: Y
authors.lastname: Du
authors.affiliation: the Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, and.
authors.forename: Manojkumar A
authors.initials: MA
authors.lastname: Puthenveedu
authors.affiliation: the Department of Psychiatry, University of California at San Francisco, San Francisco, California 94158.
authors.forename: Mark
authors.initials: M
authors.lastname: von Zastrow
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, jeffrey.benovic@jefferson.edu.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Benovic
mesh_terms: D019390:Arrestins / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C508469:ARRDC3 protein, human; D019390:Arrestins; D018343:Receptors, Adrenergic, beta-2
keywords: G protein-coupled receptor (GPCR); arrestin; arrestin domain-containing protein 3; cell signaling; endosomal signaling; receptor recycling; trafficking; β2 adrenergic receptor