exosomes在生理和疾病中通过运输各种大分子调节细胞间通讯。然而，决定exosome生物合成中其成分的调节机制尚未完全理解。我们发现一个非典型G蛋白偶联受体GPR143可以控制内质网分泌体转运所需的内质网分泌体收集复合物（ESCRT）依赖的exosome生物合成途径。GPR143与ESCRT-0亚基HRS相互作用，并促进其与货物蛋白（如EGFR）的结合，从而使其被选择性地分类进入多囊体器中的内腔泡。在人类癌细胞系中进行的定量蛋白质组学和RNA分析表明，GPR143-ESCRT途径促进分泌携带独特货物（如整合素信号蛋白）的exosomes，并在多种癌症中上调。通过在小鼠中进行功能增强和减弱的研究，我们展示了GPR143通过分泌exosomes和增加癌细胞的运动 / 侵入性通过整合素 / FAK / Src途径来促进转移的作用。这些发现提供了一个调节exosomal蛋白质组的机制，并揭示其通过促进癌细胞运动性来促进癌细胞的增殖。 版权所有 © 2023 Elsevier Inc.

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.Copyright © 2023 Elsevier Inc. All rights reserved.