Molecular Detection of Membrane Damage: Lessons from Bacteria

Mammalian cells contain many membranous organelles, among which endosomes are the initial destination for endocytosed materials. Drugs and pathogens, such as bacteria, are internalized by cells and transported to endosomes or phagosomes, then to lysosomes for degradation. Internalized drugs must escape from endosomes into the cytosol before undergoing degradation in lysosomes. However, endosomal escape is often inefficient in artificial drug delivery systems (DDSs). In contrast, many pathogens are phagocytosed and subsequently escape into the cytosol to proliferate. The studies on phagosomal escape of pathogens have revealed the molecular mechanisms through which host cells detect organelle membrane damage. In this review, we first provide an overview of bacterial endosomal and phagosomal escape, focusing on Shigella flexneri as a model organism. We then describe the current knowledge on the cellular machinery involved in sensing and repairing membrane damage, including galectins, ESCRTs, sphingomyelin, stress granules, PI4P in membrane contact sites, and Annexins. We further discuss the roles of secretory MVBs in plasma membrane repair in the Annexins and Future Perspectives sections. Research on membrane damage not only advances our understanding of cellular responses to damage caused by pathogens and artificial nanoparticles, but also informs the design of more effective DDSs.