Termination of autophagy and reformation of lysosomes regulated by mTOR.
Autophagy is an evolutionarily conserved process by which cytoplasmic proteins and organelles are catabolized. 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 autolysosomes, 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.
Yu
Li
L
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
McPhee
Christina K
CK
Zheng
Lixin
L
Mardones
Gonzalo A
GA
Rong
Yueguang
Y
Peng
Junya
J
Mi
Na
N
Zhao
Ying
Y
Liu
Zhihua
Z
Wan
Fengyi
F
Hailey
Dale W
DW
Oorschot
Viola
V
Klumperman
Judith
J
Baehrecke
Eric H
EH
Lenardo
Michael J
MJ
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D009747:Nutritional Physiological Phenomena; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014709:Vero Cells
D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; C546845:mTOR protein, rat; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases