Lysosomes are the primary degradative compartment within cells and there have been significant advances over the past decade toward understanding how lysosome homeostasis is maintained. Lysosome ...repopulation ensures sustained autophagy function, a fundamental process that protects against disease. During macroautophagy/autophagy, cellular debris is sequestered into phagophores that mature into autophagosomes, which then fuse with lysosomes to generate autolysosomes in which contents are degraded. Autophagy cannot proceed without the sufficient generation of lysosomes, and this can be achieved via their de novo biogenesis. Alternatively, during autophagic lysosome reformation (ALR), lysosomes are generated via the recycling of autolysosome membranes. During this process, autolysosomes undergo significant membrane remodeling and scission to generate membrane fragments, that mature into functional lysosomes. By utilizing membranes already formed during autophagy, this facilitates an efficient pathway for re-deriving lysosomes, particularly under conditions of prolonged autophagic flux. ALR dysfunction is emerging as an important disease mechanism including for neurodegenerative disorders such as hereditary spastic paraplegia and Parkinson disease, neuropathies including Charcot-Marie-Tooth disease, lysosome storage disorders, muscular dystrophy, metabolic syndrome, and inflammatory and liver disorders. Here, we provide a comprehensive review of ALR, including an overview of its dynamic spatiotemporal regulation by MTOR and phosphoinositides, and the role ALR dysfunction plays in many diseases.
Autophagy depends on the repopulation of lysosomes to degrade intracellular components and recycle nutrients. How cells co‐ordinate lysosome repopulation during basal autophagy, which occurs ...constitutively under nutrient‐rich conditions, is unknown. Here, we identify an endosome‐dependent phosphoinositide pathway that links PI3Kα signaling to lysosome repopulation during basal autophagy. We show that PI3Kα‐derived PI(3)P generated by INPP4B on late endosomes was required for basal but not starvation‐induced autophagic degradation. PI(3)P signals were maintained as late endosomes matured into endolysosomes, and served as the substrate for the 5‐kinase, PIKfyve, to generate PI(3,5)P2. The SNX‐BAR protein, SNX2, was recruited to endolysosomes by PI(3,5)P2 and promoted lysosome reformation. Inhibition of INPP4B/PIKfyve‐dependent lysosome reformation reduced autophagic clearance of protein aggregates during proteotoxic stress leading to increased cytotoxicity. Therefore under nutrient‐rich conditions, PI3Kα, INPP4B, and PIKfyve sequentially contribute to basal autophagic degradation and protection from proteotoxic stress via PI(3,5)P2‐dependent lysosome reformation from endolysosomes. These findings reveal that endosome maturation couples PI3Kα signaling to lysosome reformation during basal autophagy.
Synopsis
Autophagy is an adaptive response to nutrient‐poor conditions, but also regulates cells under more normal conditions. Here, sequential phosphoinositide conversion is found to mediate lysosome reformation necessary for autophagic degradation and protein aggregate clearance under nutrient‐rich conditions.
PI3Kα‐derived PI(3)P generated by INPP4B on late endosomes is required for basal but not starvation‐induced autophagic degradation.
PI(3)P is maintained on late endosomes as they mature into endolysosomes, where they act as a substrate for PI(3,5)P2 generation by PIKfyve.
PI(3,5)P2 recruits the SNX‐BAR protein SNX2 to drive lysosome reformation from endolysosomes.
Inactivation of INPP4B/PIKfyve‐dependent lysosome reformation reduces autophagic clearance of protein aggregates during proteotoxic stress, causing cell death.
Sequential phosphoinositide conversion by PI3Kα, INPP4B and PIKfyve is necessary for autophagic degradation and protein aggregate clearance under nutrient‐rich conditions.
