title: The ubiquitin-specific protease Usp4 regulates the cell surface level of the A2A receptor.
abstract: Many membrane proteins incur a folding problem during biosynthesis; only a fraction thereof is exported from the endoplasmic reticulum (ER), because quality control is stringent. This is also true for G protein-coupled receptors. Here, we identify the deubiquitinating enzyme Usp4 as an interaction partner of the A2a adenosine receptor, a Gs-coupled receptor. Usp4 binds to the carboxyl terminus of the A2A receptor and allows for its accumulation as deubiquinated protein. This relaxes ER quality control and enhances cell surface expression of functionally active receptor. The effect of Usp4 on the A2A receptor was specific because 1) it was not seen in C-terminally truncated versions of the receptor; 2) it was not mimicked by Usp14, another member of the ubiquitin-specific protease family; and 3) it was not seen with the metabotropic glutamate receptor-5, another G protein-coupled receptor with a high propensity for intracellular retention. These observations show that deubiquinating enzymes can regulate quality control in the ER.
authors.affiliation: Institute of Pharmacology, Medical University of Vienna, Währinger Str. 13a, A-1090 Vienna, Austria.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Milojevic
authors.forename: Veronika
authors.initials: V
authors.lastname: Reiterer
authors.forename: Eduard
authors.initials: E
authors.lastname: Stefan
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Korkhov
authors.forename: Mario M
authors.initials: MM
authors.lastname: Dorostkar
authors.forename: Eszter
authors.initials: E
authors.lastname: Ducza
authors.forename: Egon
authors.initials: E
authors.lastname: Ogris
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehm
authors.forename: Michael
authors.initials: M
authors.lastname: Freissmuth
authors.forename: Christian
authors.initials: C
authors.lastname: Nanoff
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D015513:Oncogene Proteins / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D043683:Receptors, Adenosine A2 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases
chemical_list: D017931:DNA Primers; D015513:Oncogene Proteins; D043683:Receptors, Adenosine A2; C486203:USP4 protein, human; D025801:Ubiquitin; D000242:Cyclic AMP; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases