Gα(s) regulates the post-endocytic sorting of G protein-coupled receptors

The role of Gα(s) in G protein-coupled receptor (GPCR) signalling at the cell surface is well established. Recent evidence has revealed the presence of Gα(s) on endosomes and its capacity to elicit GPCR-promoted signalling from this intracellular compartment. Here, we report an unconventional role for Gα(s) in the endocytic sorting of GPCRs to lysosomes. Cellular depletion of Gα(s) specifically delays the lysosomal degradation of GPCRs by disrupting the transfer of GPCRs into the intraluminal vesicles (ILVs) of multivesicular bodies (MVBs). We show that Gα(s) interacts with GASP-1 and dysbindin, two key proteins that serve as linkers between GPCRs and the ESCRT (endosomal sorting complex required for transport) machinery involved in receptor sorting into ILVs. Our findings reveal that Gα(s) plays a role in both GPCR signalling and trafficking pathways, providing another piece in the intertwining molecular network between these processes.