Bro1 proteins determine tumor immune evasion and metastasis by controlling secretion or degradation of multivesicular bodies

• Published in: Developmental cell Vol. 60; no. 15; pp. 2114 - 2130.e9
• Main Authors: Yeat, Nai Yang, Liu, Li-Heng, Chang, Yu-Hsuan, Lai, Charles Pin-Kuang, Chen, Ruey-Hwa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.08.2025
• Subjects: actin cytoskeletons; Actins - metabolism; Animals; Calcium-Binding Proteins; CapZ Actin Capping Protein; Cell Cycle Proteins; Cell Line; endocytic trafficking; Endosomal Sorting Complexes Required for Transport; ESCRT complex; exosome biogenesis; Exosomes; GTP-Binding Proteins - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Nude; Multivesicular Bodies - physiology; multivesicular body; Neoplasm Metastasis; Neoplasms, Experimental - pathology; Protein Tyrosine Phosphatases, Non-Receptor - metabolism; Tumor Escape; tumor microenvironment; actin cytoskeletons; exosome biogenesis; endocytic trafficking; tumor microenvironment; ESCRT complex; multivesicular body
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2025.03.008

Exosomes play pleiotropic tumor-promoting functions and are secreted by fusion of multivesicular bodies (MVBs) with the plasma membrane. However, MVBs are also directed to lysosomes for degradation, and the mechanism controlling different fates of MVBs remains elusive. Here, we show that the pro-tumor protein WDR4 enhances exosome secretion from mouse and human cancer cells through degrading the endosomal sorting complex required for transport (ESCRT)-associated Bro1-family protein PTPN23. Mechanistically, PTPN23 and ALIX compete for binding to syntenin, thereby directing MVBs toward degradation and secretion, respectively. ALIX, but not PTPN23, recruits actin-capping proteins CAPZA1/CAPZB to prevent branched filamentous actin (F-actin) accumulation around MVBs, thus enabling MVBs trafficking to the cell periphery for secretion. Functionally, WDR4/ALIX-dependent exosomes load a set of pro-tumor proteins through LAMP2A, thereby potentiating metastasis and immune evasion in mice. Our study highlights a previously unappreciated coupling between the biogenesis mechanism and the fate decision of MVBs and its importance in determining exosomal cargos, which have a profound impact on tumor progression. [Display omitted] •WDR4 promotes exosome secretion by inducing PTPN23 degradation•PTPN23 and ALIX govern the degradative and secretory fates of multivesicular bodies (MVBs), respectively•ALIX blocks excessive actin polymerization around MVBs to promote MVB trafficking•WDR4/ALIX-dependent exosomes load pro-tumor cargos to facilitate tumor progression Yeat et al. show that distinct multivesicular body (MVB) biogenesis mechanisms control the fates of MVBs between lysosome degradation and exosome secretion by differentially regulating F-actin around MVBs. The WDR4 pro-tumor protein impacts this MVB decision mechanism to promote exosome secretion, in turn affecting metastasis and tumor immune evasion.