Novel mechanisms in the regulation of G protein-coupled receptor trafficking to the plasma membrane.
β(2)-adrenergic receptors (β(2)-AR) are low abundance, integral membrane proteins that mediate the effects of catecholamines at the cell surface. Whereas the processes governing desensitization of activated β(2)-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 β(2)-AR mRNA to the peripheral cytoplasmic regions is critical for receptor localization to the plasma membrane. β(2)-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, β(2)-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 β(2)-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.
Tholanikunnel
Baby G
BG
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA. tholanik@musc.edu
Joseph
Kusumam
K
Kandasamy
Karthikeyan
K
Baldys
Aleksander
A
Raymond
John R
JR
Luttrell
Louis M
LM
McDermott
Paul J
PJ
Fernandes
Daniel J
DJ
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001692:Biological Transport; D016466:CHO Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D006801:Humans; D008954:Models, Biological; D011132:Polyribosomes / Q000378:metabolism; D011485:Protein Binding; D021382:Protein Sorting Signals; D016601:RNA-Binding Proteins / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D021382:Protein Sorting Signals; D016601:RNA-Binding Proteins; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled