Kim Su Bin, Lee Ji Su, Jung Chan Hoon, Cho Eun Hye, Seo Ho Seok, Lee Gee Eun, Kim Hye Yeon, Lee Su Jin, Lee Min Ju, Oh Hans Jin-Young, Heo Ah Jung, Han Do Hyun, Kwon Yong Tae, Ji Chang Hoon
Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea.
Department of Transdisciplinary Medicine, Seoul National University Hospital, 71 Daehakro, Seoul, Republic of Korea.
iScience. 2025 May 10;28(6):112637. doi: 10.1016/j.isci.2025.112637. eCollection 2025 Jun 20.
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.
癌细胞来源的外泌体是细胞间通讯的多功能介质，其货物会根据各种应激条件动态装载。在本研究中，我们证明在氧化应激下，癌细胞分泌的外泌体通过精氨酸/N-端规则途径诱导邻近细胞凋亡。在这种机制中，Rab相互作用溶酶体蛋白（RILP）在天冬氨酸75处被切割以响应氧化应激，这需要ATE1 R转移酶。切割后的RILP将ESCRT-II蛋白VPS22和VPS36招募到内体，腔内小泡从内体中内陷产生外泌体。通过蛋白质组学分析，我们还证明氧化应激下癌细胞分泌的外泌体富含凋亡蛋白，包括促凋亡和抗炎细胞因子膜联蛋白A1（ANXA1）。这些外泌体以精氨酸/N-端规则途径依赖的方式诱导转运ANXA1的正常癌细胞凋亡。我们的结果表明，精氨酸/N-端规则途径在氧化应激下调节癌细胞中外泌体介导的凋亡，这是ANXA1依赖RILP分泌的基础。
