Sequence-directed concentration of G protein-coupled receptors in COPII vesicles

G protein-coupled receptors (GPCRs) constitute the largest superfamily of plasma membrane signaling proteins. However, virtually nothing is known about their recruitment to COPII vesicles for forward delivery after synthesis in the endoplasmic reticulum (ER). Here, we demonstrate that some GPCRs are highly concentrated at ER exit sites (ERES) before COPII budding. Angiotensin II type 2 receptor (AT2R) and CXCR4 concentration are directed by a di-acidic motif and a 9-residue domain, respectively, and these motifs also control receptor ER-Golgi traffic. We further show that AT2R interacts with Sar1 GTPase and that distinct GPCRs have different ER-Golgi transport rates via COPII which is independent of their concentration at ERES. Collectively, these data demonstrate that GPCRs can be actively captured by COPII via specific motifs and direct interaction with COPII components that in turn affects their export dynamics, and provide important insights into COPII targeting and forward trafficking of nascent GPCRs.