GPR143 controls ESCRT-dependent exosome biogenesis and promotes cancer metastasis

• Published in: Developmental cell 2023-02, Vol.58 (4), p.320-334.e8
• Main Authors: Lee, Yu Jin, Shin, Kyeong Jin, Jang, Hyun-Jun, Ryu, Jin-Sun, Lee, Chae Young, Yoon, Jong Hyuk, Seo, Jeong Kon, Park, Sabin, Lee, Semin, Je, A Reum, Huh, Yang Hoon, Kong, Sun-Young, Kwon, Taejoon, Suh, Pann-Ghill, Chae, Young Chan
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport; breast cancer; Endosomal Sorting Complexes Required for Transport - genetics; Endosomal Sorting Complexes Required for Transport - metabolism; exosomal protein sorting; exosome biogenesis; Exosomes - metabolism; Eye Proteins - metabolism; GPR143; HRS; Humans; melanoma; Membrane Glycoproteins - metabolism; metastasis; Mice; Multivesicular Bodies - metabolism; MVB; Neoplasms - metabolism; Protein Transport; Proteomics
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2023.01.006

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. [Display omitted] •GPR143 regulates ESCRT-dependent exosome production•GPR143 recruits HRS to endosomes to modulate interaction with cargo protein•GPR143 regulates protein sorting in ILVs and alters exosomal proteome composition•Exosomal integrins activate the cell motility signaling pathway to promote metastasis Lee et al. find that GPR143, an atypical GPCR, controls the ESCRT-dependent exosome biogenesis pathway, which determines exosomal protein cargo composition. In cancer, GPR143 expression facilitates secretion of oncogenic exosomes, which contain integrins that promote cell motility and cancer metastasis.