The role of lysosomes in metabolic and autoimmune diseases

Lysosomes are catabolic organelles that contribute to the degradation of intracellular constituents through autophagy and of extracellular components through endocytosis, phagocytosis and macropinocytosis. They also have roles in secretory mechanisms, the generation of extracellular vesicles and certain cell death pathways. These functions make lysosomes central organelles in cell homeostasis, metabolic regulation and responses to environment changes including nutrient stresses, endoplasmic reticulum stress and defects in proteostasis. Lysosomes also have important roles in inflammation, antigen presentation and the maintenance of long-lived immune cells. Their functions are tightly regulated by transcriptional modulation via TFEB and TFE3, as well as by major signalling pathways that lead to activation of mTORC1 and mTORC2, lysosome motility and fusion with other compartments. Lysosome dysfunction and alterations in autophagy processes have been identified in a wide variety of diseases, including autoimmune, metabolic and kidney diseases. Deregulation of autophagy can contribute to inflammation, and lysosomal defects in immune cells and/or kidney cells have been reported in inflammatory and autoimmune pathologies with kidney involvement. Defects in lysosomal activity have also been identified in several pathologies with disturbances in proteostasis, including autoimmune and metabolic diseases such as Parkinson disease, diabetes mellitus and lysosomal storage diseases. Targeting lysosomes is therefore a potential therapeutic strategy to regulate inflammation and metabolism in a variety of pathologies. In this Review, the authors describe the roles of lysosomes in cellular clearance, autophagy, cell signalling, nutrient sensing and metabolic adaptation. They also discuss lysosome abnormalities in metabolic and autoimmune diseases and potential lysosome-targeting therapeutic strategies. Key points Lysosomes are versatile organelles that can associate with several other cell compartments, resulting in a variety of functions including roles in autophagy, endocytosis, phagocytosis, secretory mechanisms and cell death pathways. Lysosomes are dynamic, motile organelles that respond to intracellular and extracellular stimuli and are subject to numerous changes according to their environment; the composition, number and size of lysosomes are finely regulated. Lysosomes have vital functions in cell homeostasis and metabolic regulation as well as in the immune system