PTPN23 downregulation by WDR4 Determines the Exosome Secretion Fate of MVB to Promote Cancer Metastasis and Immune Evasion

Exosomes play pleiotropic tumor-promoting functions and are originated from a diversion of endocytic pathway. In late endocytic trafficking, multivesicular bodies (MVBs) are directed to lysosomes for degradation or secreted as exosomes. However, the mechanism controlling different fates of MVBs remains elusive. Here, we show that WDR4 promotes exosome secretion through the degradation of PTPN23, an ESCRT-associated Bro1-family protein. Mechanistically, PTPN23 competes with ALIX, another Bro1-family protein, for binding syntenin, thus enabling PTPN23 and ALIX for promoting MVBs towards degradation and secretion, respectively. Furthermore, ALIX uniquely recruits actin-capping/severing proteins to prevent F-actin accumulation around MVBs, thereby facilitating MVBs trafficking to cell periphery for secretion. Functionally, the WDR4/ALIX-dependent exosomes preferentially load pro-tumor proteins including PTK2, MCAM and NRP1, thereby enhancing metastasis and immune evasion. This study highlights a previously unprecedented mechanism for regulating MVBs fates and exosome cargos, which have potential broad impacts on tuning exosome production and devising cancer therapeutic strategy.