Novel Mechanisms in the Regulation of G Protein-coupled Receptor Trafficking to the Plasma Membrane

• Published in: The Journal of biological chemistry 2010-10, Vol.285 (44), p.33816-33825
• Main Authors: Tholanikunnel, Baby G., Joseph, Kusumam, Kandasamy, Karthikeyan, Baldys, Aleksander, Raymond, John R., Luttrell, Louis M., McDermott, Paul J., Fernandes, Daniel J.
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Surface - metabolism; Biological Transport; Cell Line, Tumor; Cell Membrane - metabolism; Cell Surface Receptor; CHO Cells; Cricetinae; Cricetulus; ELAV Proteins; ELAV-Like Protein 1; G Protein-coupled Receptors (GPCR); Gene Expression; Humans; HuR; Models, Biological; mRNA Localization; Polyribosomes - metabolism; Protein Binding; Protein Sorting Signals; Receptor Regulation; Receptors, Adrenergic, beta-2 - metabolism; Receptors, G-Protein-Coupled - metabolism; RNA; RNA Transport; RNA-binding Proteins; RNA-Binding Proteins - metabolism; Signal Transduction; Translational Control; β2-Adrenergic Receptor
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.168229

β2-Adrenergic receptors (β2-AR) are low abundance, integral membrane proteins that mediate the effects of catecholamines at the cell surface. Whereas the processes governing desensitization of activated β2-ARs and their subsequent removal from the cell surface have been characterized in considerable detail, little is known about the mechanisms controlling trafficking of neo-synthesized receptors to the cell surface. Since the discovery of the signal peptide, the targeting of the integral membrane proteins to plasma membrane has been thought to be determined by structural features of the amino acid sequence alone. Here we report that localization of translationally silenced β2-AR mRNA to the peripheral cytoplasmic regions is critical for receptor localization to the plasma membrane. β2-AR mRNA is recognized by the nucleocytoplasmic shuttling RNA-binding protein HuR, which silences translational initiation while chaperoning the mRNA-protein complex to the cell periphery. When HuR expression is down-regulated, β2-AR mRNA translation is initiated prematurely in perinuclear polyribosomes, leading to overproduction of receptors but defective trafficking to the plasma membrane. Our results underscore the importance of the spatiotemporal relationship between β2-AR mRNA localization, translation, and trafficking to the plasma membrane, and establish a novel mechanism whereby G protein-coupled receptor (GPCR) responsiveness is regulated by RNA-based signals.