Termination of autophagy and reformation of lysosomes regulated by mTOR

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Abstract
During autophagy, double-membrane autophagosomes sequester intracellular components and then fuse with lysosomes to form autolysosomes in which cargo is degraded. Under starvation conditions, the nutrient-responsive kinase, target of rapamycin (TOR), is inhibited, which results in an induction of autophagy. In this study, Yu et al. report a negative feedback mechanism by which lysosomes are reformed after the termination of autophagy. They demonstrate that upon prolonged starvation conditions, mTOR is reactivated, which attenuates autophagy and results in the formation of tubules and vesicles that extrude from autolysosomes. These mature into functional lysosomes, thereby restoring lysosome numbers in the cell. This feedback mechanism tightly couples nutritional status with the induction and termination of autophagy. When cells are starved, the enzyme TOR is inhibited, inducing autophagy. In this process, autophagosomes sequester intracellular components and then fuse with lysosomes, producing autolysosomes in which cargo is degraded to regenerate nutrients. Now, a mechanism is revealed by which lysosomes are re-formed. When starvation conditions are prolonged, mTOR is re-activated; this attenuates autophagy and results in tubules and vesicles extruding from the autolysosome and maturing into functional lysosomes. Autophagy is an evolutionarily conserved process by which cytoplasmic proteins and organelles are catabolized1,2. During starvation, the protein TOR (target of rapamycin), a nutrient-responsive kinase, is inhibited, and this induces autophagy. In autophagy, double-membrane autophagosomes envelop and sequester intracellular components and then fuse with lysosomes to form autolysosomes, which degrade their contents to regenerate nutrients. Current models of autophagy terminate with the degradation of the autophagosome cargo in autolysosomes3,4,5, but the regulation of autophagy in response to nutrients and the subsequent fate of the autolysosome are poorly understood. Here we show that mTOR signalling in rat kidney cells is inhibited during initiation of autophagy, but reactivated by prolonged starvation. Reactivation of mTOR is autophagy-dependent and requires the degradation of autolysosomal products. Increased mTOR activity attenuates autophagy and generates proto-lysosomal tubules and vesicles that extrude from autolysosomes and ultimately mature into functional lysosomes, thereby restoring the full complement of lysosomes in the cell—a process we identify in multiple animal species. Thus, an evolutionarily conserved cycle in autophagy governs nutrient sensing and lysosome homeostasis during starvation.