Abstract
The Gα(s) subunit is classically involved in the signal transduction of G protein-coupled receptors (GPCRs) at the plasma membrane. Recent evidence has revealed noncanonical roles for Gα(s) in endosomal sorting of receptors to lysosomes. However, the mechanism of action of Gα(s) in this sorting step is still poorly characterized. Here, we report that Gα(s) interacts with ubiquitin to regulate the endosomal sorting of receptors for lysosomal degradation. We reveal that the N-terminal extremity of Gα(s) contains a ubiquitin-interacting motif (UIM), a sorting element usually found in the endosomal sorting complex required for transport (ESCRT) machinery responsible for sorting ubiquitinated receptors into intraluminal vesicles (ILVs) of multivesicular bodies (MVBs). Mutation of the UIM in Gα(s) confirmed the importance of ubiquitin interaction for the sorting of epidermal growth factor receptor (EGFR) into ILVs for lysosomal degradation. These findings demonstrate a role for Gα(s) as an integral component of the ubiquitin-dependent endosomal sorting machinery and highlight the dual role of Gα(s) in receptor trafficking and signaling for the fine-tuning of the cellular response.