Regulation of β2-Adrenergic Receptor Maturation and Anterograde Trafficking by an Interaction with Rab Geranylgeranyltransferase MODULATION OF Rab GERANYLGERANYLATION BY THE RECEPTOR

Previous reports by us and others demonstrated that G protein-coupled receptors interact functionally with Rab GTPases. Here, we show that the beta(2)-adrenergic receptor (beta(2)AR) interacts with the Rab geranylgeranyltransferase alpha-subunit (RGGTA). Confocal microscopy showed that beta(2)AR co-localizes with RGGTA in intracellular compartments and at the plasma membrane. Site-directed mutagenesis revealed that RGGTA binds to the (LL340)-L-339 motif in the beta(2)AR C terminus known to be involved in the transport of the receptor from the endoplasmic reticulum to the cell surface. Modulation of the cellular levels of RGGTA protein by overexpression or siRNA-mediated knockdown of the endogenous protein demonstrated that RGGTA has a positive role in the maturation and anterograde trafficking of the beta(2)AR, which requires the interaction of RGGTA with the beta(2)AR (LL340)-L-339 motif. Furthermore, the beta(2)AR modulates the geranylgeranylation of Rab6a, Rab8a, and Rab Ha, but not of other Rab proteins tested in this study. Regulation of Rab geranylgeranylation by the beta(2)AR was dependent on the RGGTA-interacting (LL340)-L-339 motif. Interestingly, a RGGTA-Y107F mutant was unable to regulate Rab geranylgeranylation but still promoted beta(2)AR maturation, suggesting that RGGTA may have functions independent of Rab geranylgeranylation. We demonstrate for the first time an interaction between a transmembrane receptor and RGGTA which regulates the maturation and anterograde transport of the receptor, as well as geranylgeranylation of Rab GTPases.