The ubiquitin-specific protease Usp4 regulates the cell surface level of the A2A receptor.
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.
Milojevic
Tetyana
T
Institute of Pharmacology, Medical University of Vienna, Währinger Str. 13a, A-1090 Vienna, Austria.
Reiterer
Veronika
V
Stefan
Eduard
E
Korkhov
Vladimir M
VM
Dorostkar
Mario M
MM
Ducza
Eszter
E
Ogris
Egon
E
Boehm
Stefan
S
Freissmuth
Michael
M
Nanoff
Christian
C
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
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