GPR143 controls 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 find that GPR143, an atypical GPCR, controls the endosomal sorting complex required for the 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 intraluminal vesicles (ILVs) in multivesicular bodies (MVBs). GPR143 is elevated in multiple cancers, and quantitative proteomic and RNA profiling of exosomes in human cancer cell lines showed that the GPR143-ESCRT pathway promotes secretion of exosomes that carry unique cargo, including integrins signaling proteins. Through gain- and loss-of-function studies in mice, we show that GPR143 promotes metastasis by secreting exosomes and increasing cancer cell motility/invasion through the integrin/FAK/Src pathway. These findings provide a mechanism for regulating the exosomal proteome and demonstrate its ability to promote cancer cell motility.