Lysosomal Machinery Drives Extracellular Acidification to Direct Non-apoptotic Cell Death

Cell death is a fundamental aspect of development, homeostasis, and disease; yet, our understanding of non-apoptotic forms of cell death is limited. One such form is phagoptosis, in which one cell utilizes phagocytosis machinery to kill another cell that would otherwise continue living. We have previously identified a non-autonomous requirement of phagocytosis machinery for the developmental programmed cell death of germline nurse cells in the Drosophila ovary; however, the precise mechanism of death remained elusive. Here, we show that lysosomal machinery acting in epithelial follicle cells is used to non-autonomously induce the death of nearby germline cells. Stretch follicle cells recruit V-ATPases and chloride channels to their plasma membrane to extracellularly acidify the germline and release cathepsins that destroy the nurse cells. Our results reveal a role for lysosomal machinery acting at the plasma membrane to cause the death of neighboring cells, providing insight into mechanisms driving non-autonomous cell death. [Display omitted] •Lysosome-associated genes are required in follicle cells for nurse cell death•V-ATPases localize to the plasma membrane of follicle cells to acidify nurse cells•Cathepsin L is released by follicle cells and promotes nurse cell DNA degradation Mondragon et al. show that V-ATPase proton pumps localize to the plasma membrane of follicle cells and promote extracellular acidification to eliminate adjacent nurse cells in the Drosophila ovary. The follicle cells subsequently release cathepsins by exocytosis into the nurse cells to promote their final degradation.