GPR143 regulates ESCRT-dependent exosome biogenesis and promotes cancer metastasis

Exosomes transport a variety of macromolecules and modulate intercellular communication in physiology and disease. However, the regulation mechanisms that determine exosome contents during exosome biogenesis remain poorly understood. Here, we identify GPR143, an atypical GPCR, as a regulator of the endosomal sorting complex required for transport (ESCRT)-dependent exosome biogenesis pathway. GPR143 interacts with HRS (an ESCRT-0 Subunit) and promotes its association to cargo proteins, such as EGFR, which subsequently enables selective protein sorting into intralumenal vesicles (ILVs) in multivesicular bodies (MVBs). GPR143 is elevated in multiple cancers and quantitative proteomic and RNA profiling of exosomes revealed the GPR143-ESCRT pathway promotes secretion of exosomes that carry unique cargo, including integrins signaling proteins. By gain- and loss-of-function studies, we reveal GPR143 promotes metastasis by secreting exosomes and increasing cell motility/invasion through the integrin/FAK/Src pathway. These finding uncover a mechanism that regulates the exosomal proteome and demonstrate its ability to promote cancer metastasis.