The Arg/N-degron pathway mediates the secretion of apoptotic exosomes under oxidative stress in cancer cell

Exosomes from cancer cells are versatile mediators of cell-to-cell communication, whose cargoes are dynamically loaded in response to various stress conditions. In this study, we demonstrate that under oxidative stress, cancer cells secrete exosomes that induce apoptosis in neighboring cells via the Arg/N-degron pathway. In this mechanism, Rab interacting lysosomal protein (RILP) is cleaved at Asp75 in response to oxidative stress which requires ATE1 R-transferase. The cleaved form of RILP recruits the ESCRT-II proteins VPS22 and VPS36 to endosomes from which the interluminal vesicles are invaginated generating exosomes. By using proteomics analyses, we also demonstrate that exosomes secreted from cancer cells upon oxidative stress are enriched apoptotic proteins including pro-apoptotic and anti-inflammatory cytokine ANXA1. These exosomes induce apoptosis of normal cancer cells transporting ANXA1 in an Arg/N-degron pathway-dependent manner. Our results show that the Arg/N-degron pathway modulates exosome-mediated apoptosis in cancer cells under oxidative stress underlying RILP-dependent secretion of ANXA1.