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Termination of autophagy and reformation of lysosomes regulated by mTOR


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.

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Figure 1: Lysosome homeostasis during starvation.
Figure 2: Proto-lysosome formation and maturation.
Figure 3: Reactivation of mTOR inhibits autophagy and initiates lysosome reformation.
Figure 4: Autophagic lysosome reformation.


  1. Mizushima, N. Autophagy: process and function. Genes Dev. 21, 2861–2873 (2007)

    Article  CAS  Google Scholar 

  2. Xie, Z. & Klionsky, D. J. Autophagosome formation: core machinery and adaptations. Nature Cell Biol. 9, 1102–1109 (2007)

    Article  CAS  Google Scholar 

  3. Jager, S. et al. Role for Rab7 in maturation of late autophagic vacuoles. J. Cell Sci. 117, 4837–4848 (2004)

    Article  Google Scholar 

  4. Jahreiss, L., Menzies, F. M. & Rubinsztein, D. C. The itinerary of autophagosomes: from peripheral formation to kiss-and-run fusion with lysosomes. Traffic 9, 574–587 (2008)

    Article  CAS  Google Scholar 

  5. Kimura, S., Noda, T. & Yoshimori, T. Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3, 452–460 (2007)

    Article  CAS  Google Scholar 

  6. Scott, R. C., Schuldiner, O. & Neufeld, T. P. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7, 167–178 (2004)

    Article  CAS  Google Scholar 

  7. Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006)

    Article  CAS  Google Scholar 

  8. Massey, A. C., Follenzi, A., Kiffin, R., Zhang, C. & Cuervo, A. M. Early cellular changes after blockage of chaperone-mediated autophagy. Autophagy 4, 442–456 (2008)

    Article  CAS  Google Scholar 

  9. Mizushima, N. & Kuma, A. Autophagosomes in GFP-LC3 transgenic mice. Methods Mol. Biol. 445, 119–124 (2008)

    Article  CAS  Google Scholar 

  10. Dennis, P. B. et al. Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102–1105 (2001)

    Article  ADS  CAS  Google Scholar 

  11. Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585–595 (2004)

    Article  CAS  Google Scholar 

  12. Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008)

    Article  ADS  CAS  Google Scholar 

  13. Yu, L., Lenardo, M. J. & Baehrecke, E. H. Autophagy and caspases: a new cell death program. Cell Cycle 3, 1124–1126 (2004)

    CAS  PubMed  Google Scholar 

  14. Yu, L., Strandberg, L. & Lenardo, M. J. The selectivity of autophagy and its role in cell death and survival. Autophagy 4, 567–573 (2008)

    Article  Google Scholar 

  15. Yu, L. et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500–1502 (2004)

    Article  ADS  CAS  Google Scholar 

  16. Slot, J. W. & Geuze, H. J. Cryosectioning and immunolabeling. Nature Protocols 2, 2480–2491 (2007)

    Article  CAS  Google Scholar 

  17. Bidère, N. et al. Casein kinase 1α governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival. Nature 458, 92–96 (2009)

    Article  ADS  Google Scholar 

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We thank the National Institute of Allergy and Infectious Diseases (NIAID) imaging core facility and Olympus China for technical support; O. Schwartz, J. Kabat, L. Koo, M. Czapiga (Bio-imaging facility (BIF), NIAID, NIH) and Q. Dong (Olympus China) for assistance with confocal microscopy and imaging processing; K. Nagashima and M. J. de la Cruz (NCI) for TEM analyses: J. Lippincott-Schwartz, H Bernstein, and J. Bonifacino for helpful discussions; D. Yamamoto, G. Davis and H. Kramer for constructs and fly strains; and M. v. Peski and R. Scriwanek for assistance with the preparation of the EM figures. This research was supported by the Division of Intramural Research of the NIAID, NIH, Department of Health and Human Services and NIH Grant GM079431 to E.B., 973 program 2010CB833704, NSF grant 20091300700, and Tsinghua University grant 20091081391 to Y.L. J.K. is the recipient of VICI grant 918.56.611 of the Netherlands Organisation for Scientific Research (NWO).

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Authors and Affiliations



L.Y. first observed lysosome reformation at the end of autophagy, autophagy dependent mTOR reactivation and performed the original characterization of the phenomenon. G.A.M. and D.W.H. made critical DNA constructs and designed the live imaging experiments. L.Z. performed the density gradient analyses. C.K.M. performed Drosophila experiments. V.O. performed immuno-TEM analyses. M.J.L. and L.Y. wrote the manuscript and J.P., Y.R., N.M., Y.Z., Z.L. and F.W. helped in the manuscript revision experiments. Most of the experiments were performed by L.Y. and were conceived by L.Y., E.H.B. and M.J.L. J.K. conceived and executed certain E.M. experiments. All authors wrote, discussed and revised the manuscript.

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Correspondence to Michael J. Lenardo.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures S1-S19 with legends, full legends for Supplementary Movies 1-3 and Supplementary Methods. (PDF 4940 kb)

Supplementary Movie 1

This movie shows that multiple lysosomes fuse with GFP-LC3-labeled autophagic vesicle (see movie legend S1 in Supplementary Information file). (AVI 5489 kb)

Supplementary Movie 2

This movie shows tubules extending from autolysosomal membranes (arrow) and small Lamp1-positive vesicles pinching off from the tips of tubules (see movie legend S2 in Supplementary Information file). (MOV 2730 kb)

Supplementary Movie 3

This movie shows tubules breaking away from autolysosomes and condensing into Lamp1-positive vesicles (see movie legend S3 in Supplementary Information file). (AVI 3733 kb)

The Supplementary Information file and this table of contents were updated and replaced on 07 July 2010.

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Yu, L., McPhee, C., Zheng, L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942–946 (2010).

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