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GPR143 regulates ESCRT-dependent exosome biogenesis and promotes cancer metastasis

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Early Embryonic Cell

SUBMITTER: YU JIN LEE

LAB HEAD: Young Chan Chae

PROVIDER: PXD031515 | Pride | 2022-12-20

REPOSITORIES: Pride

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Project description:BACKGROUND: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles (EVs) including small EVs, or exosomes and their molecular cargo are known to modulate cell to cell communication during multiple cardiac diseases. However, the role of systemic EV biogenesis inhibition in the models of HF is not well documented and remains unclear. METHODS: We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of Tipifarnib (Tip), a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a, nSmase2 and Alix) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery, were randomly assigned to groups with and without Tip treatment (10 mg/kg three times/week) and monitored for 8 weeks and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies. RESULTS: TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular (LV) dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced LV dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of Tip in TAC mice reduced circulating exosomes to baseline and remarkably improved LV functions, hypertrophy, and fibrosis. Tip treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR331-5p which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR331-5p is crucial for inhibiting fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR331-5p that acts as potent repressor for one of the fibrotic mechanisms mediated by HOXC8. CONCLUSIONS: Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling to HF.

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GPR143 regulates ESCRT-dependent exosome biogenesis and promotes cancer metastasis

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