Gα_s protein binds ubiquitin to regulate epidermal growth factor receptor endosomal sorting

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.