title: The golgi-associated PDZ domain protein PIST/GOPC stabilizes the β1-adrenergic receptor in intracellular compartments after internalization.
abstract: Many G-protein-coupled receptors carry C-terminal ligand motifs for PSD-95/discs large/ZO-1 (PDZ) domains; via interaction with PDZ domain-containing scaffold proteins, this allows for integration of receptors into signaling complexes. However, the presence of PDZ domain proteins attached to intracellular membranes suggests that PDZ-type interactions may also contribute to subcellular sorting of receptors. The protein interacting specifically with Tc10 (PIST; also known as GOPC) is a trans-Golgi-associated protein that interacts through its single PDZ domain with a variety of cell surface receptors. Here we show that PIST controls trafficking of the interacting β1-adrenergic receptor both in the anterograde, biosynthetic pathway and during postendocytic recycling. Overexpression and knockdown experiments show that PIST leads to retention of the receptor in the trans-Golgi network (TGN), to the effect that overexpressed PIST reduces activation of the MAPK pathway by β1-adrenergic receptor (β1AR) agonists. Receptors can be released from retention in the TGN by coexpression of the plasma membrane-associated scaffold PSD-95, which allows for transport of receptors to the plasma membrane. Stimulation of β1 receptors and activation of the cAMP pathway lead to relocation of PIST from the TGN to an endosome-like compartment. Here PIST colocalizes with SNX1 and the internalized β1AR and protects endocytosed receptors from lysosomal degradation. In agreement, β1AR levels are decreased in hippocampi of PIST-deficient mice. Our data suggest that PIST contributes to the fine-tuning of β1AR sorting both during biosynthetic and postendocytic trafficking.
authors.affiliation: From the Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany and.
authors.forename: Judith
authors.initials: J
authors.lastname: Koliwer
authors.affiliation: Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California at San Francisco School of Medicine, San Francisco, California 94158.
authors.forename: Minjong
authors.initials: M
authors.lastname: Park
authors.affiliation: From the Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany and.
authors.forename: Carola
authors.initials: C
authors.lastname: Bauch
authors.affiliation: Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California at San Francisco School of Medicine, San Francisco, California 94158.
authors.forename: Mark
authors.initials: M
authors.lastname: von Zastrow
authors.affiliation: From the Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany and Kreienkamp@uke.de.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Kreienkamp
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000235:genetics; D011992:Endosomes / Q000235:genetics; D005786:Gene Expression Regulation; D000077614:Golgi Matrix Proteins; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D054731:PDZ Domains / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D021601:trans-Golgi Network / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C434484:GOPC protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D018342:Receptors, Adrenergic, beta-1; D043562:Receptors, G-Protein-Coupled
keywords: Endocytosis; G-protein-coupled Receptor (GPCR); Golgi; PDZ Domain; Receptor Recycling