Molecular Detection of Membrane Damage in Mammalian Cells

Mammalian cells contain numerous membrane-bound organelles, among which endosomes serve as the initial destination for endocytosed materials. Drugs and pathogens are internalized by cells and transported to endosomes or phagosomes, and are subsequently delivered to lysosomes for degradation. Therefore, internalized drugs must escape from endosomes into the cytosol before lysosomal degradation occurs. However, endosomal escape is often inefficient in artificial drug delivery systems (DDSs). In contrast, many pathogens such as bacteria are phagocytosed and subsequently escape into the cytosol where they proliferate successfully. Studies on bacterial phagosomal escape have revealed molecular mechanisms by which host cells detect damage to organelle membrane. These host cellular machineries for sensing membrane damage can also detect membrane damage caused by artificial drugs. In this review, we summarize current knowledge of the cellular machinery involved in sensing membrane damage, including galectins, ESCRT complexes, sphingomyelin, stress granules, phosphatidylinositol 4-phosphate (PI4P) at membrane contact sites, and annexins. Although the aim of this review is to identify the molecules involved in endosomal membrane damage, many of these molecules were initially discovered through studies of bacterial infection and damage to the plasma membrane or lysosomes. Research on membrane damage not only advances our understanding of cellular responses to organelle damage, but also provides insights into the toxicity induced by inorganic materials and contributes to the rational design of more effective DDSs.