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Original Article

The Ubiquitin-Specific Protease Usp4 Regulates the Cell Surface Level of the A_2a Receptor

Tetyana Milojevi, Veronika Reiterer, Eduard Stefan, Vladimir M. Korkhov, Mario M. Dorostkar, Eszter Ducza, Egon Ogris, Stefan Boehm, Michael Freissmuth, and Christian Nanoff

Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology (T.M., V.R., E.S., V.M.K., M.M.D., E.D., S.B., M.F., C.N.) and Department of Medical Biochemistry at the Vienna Biocenter (E.O.), Medical University of Vienna, Vienna, Austria

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 A_2a adenosine receptor, a G_s-coupled receptor. Usp4 binds to the carboxyl terminus of the A_2A 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 A_2A 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.

Address correspondence to: Dr. Michael Freissmuth, Institute of Pharmacology, Medical University of Vienna, Währinger Str. 13a, A-1090 Vienna, Austria. E-mail: michael.freissmuth{at}meduniwien.ac.at

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