Cytopurgosis: an export mechanism for organelle clearance that compensates for impaired lysosomal degradation

Abstract

Cells must eliminate various unwanted organelles to maintain homeostasis, yet how they achieve this when their primary degradation system, the lysosome, is impaired remains poorly understood. Here, we discover cytopurgosis, a lysosome-independent organelle-removal pathway that expels multiple organelles, including entire lysosomes, within large extracellular vesicles that we termed "purgasomes". Cytopurgosis transitions from a basal process to a robust stress response under conditions of lysosomal overload, including in a genetic model of Niemann-Pick type C1 disease. Mechanistically, this lysosomal stress reduces plasma membrane PI(4,5)P₂ levels, triggering phosphatidylethanolamine externalization, which drives purgasome formation through plasma membrane budding. Importantly, cytopurgosis exhibits cargo selectivity, enabling cells to selectively sort and eject overloaded lysosomes dependent on RAB-7 and UNC-116/Kinesin-1, which is crucial for preserving lysosomal homeostasis. Our findings establish cytopurgosis as a fundamental organelle disposal pathway that complements intracellular degradation and reveal purgasome-mediated lysosome export as a previously-unknown lysosomal quality control mechanism.