Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Lysosomal positioning coordinates cellular nutrient responses

Nature Cell Biology volume 13, pages 453–460 (2011)Cite this article

Subjects

Abstract

mTOR (mammalian target of rapamycin) signalling and macroautophagy (henceforth autophagy) regulate numerous pathological and physiological processes, including cellular responses to altered nutrient levels. However, the mechanisms regulating mTOR and autophagy remain incompletely understood. Lysosomes are dynamic intracellular organelles1,2 intimately involved both in the activation of mTOR complex 1 (mTORC1) signalling and in degrading autophagic substrates3,4,5,6,7,8. Here we report that lysosomal positioning coordinates anabolic and catabolic responses with changes in nutrient availability by orchestrating early plasma-membrane signalling events, mTORC1 signalling and autophagy. Activation of mTORC1 by nutrients correlates with its presence on peripheral lysosomes that are physically close to the upstream signalling modules, whereas starvation causes perinuclear clustering of lysosomes, driven by changes in intracellular pH. Lysosomal positioning regulates mTORC1 signalling, which in turn influences autophagosome formation. Lysosome positioning also influences autophagosome–lysosome fusion rates, and thus controls autophagic flux by acting at both the initiation and termination stages of the process. Our findings provide a physiological role for the dynamic state of lysosomal positioning in cells as a coordinator of mTORC1 signalling with autophagic flux.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Changes in mTORC1 signalling in response to starvation correlate with lysosomal positioning.
Figure 2: Factors changing lysosomal positioning also affect mTORC1 signalling.
Figure 3: Lysosomal positioning regulates recovery of mTOR signalling after starvation.
Figure 4: Nutrients control lysosomal positioning by modulating pHi and lysosomal levels of KIF2 and ARL8B.
Figure 5: Lysosomal positioning modulates autophagy.

Similar content being viewed by others

References

  1. Heuser, J. Changes in lysosome shape and distribution correlated with changes in cytoplasmic pH. J. Cell Biol. 108, 855–864 (1989).

    Article  CAS  Google Scholar 

  2. Luzio, J. P., Pryor, P. R. & Bright, N. A. Lysosomes: fusion and function. Nat. Rev. Mol. Cell Biol. 8, 622–632 (2007).

    Article  CAS  Google Scholar 

  3. Sancak, Y. et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290–303 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. 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 

  6. Kimura, S., Noda, T. & Yoshimori, T. Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell Struct. Funct. 33, 109–122 (2008).

    Article  CAS  Google Scholar 

  7. Klionsky, D. J. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol. 8, 931–937 (2007).

    Article  CAS  Google Scholar 

  8. Ravikumar, B. et al. Mammalian macroautophagy at a glance. J. Cell Sci. 122, 1707–1711 (2009).

    Article  CAS  Google Scholar 

  9. Sengupta, S., Peterson, T. R. & Sabatini, D. M. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol. Cell 40, 310–322 (2010).

    Article  CAS  Google Scholar 

  10. Tee, A. R., Anjum, R. & Blenis, J. Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and-independent phosphorylation of tuberin. J. Biol. Chem. 278, 37288–37296 (2003).

    Article  CAS  Google Scholar 

  11. Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C. & Blenis, J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268 (2003).

    Article  CAS  Google Scholar 

  12. Soulard, A. & Hall, M. N. SnapShot: mTOR signaling. Cell 129, 434 (2007).

    Article  Google Scholar 

  13. Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935–945 (2008).

    Article  CAS  Google Scholar 

  14. Cai, S. L. et al. Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. J. Cell Biol. 173, 279–289 (2006).

    Article  CAS  Google Scholar 

  15. Jiang, H. & Vogt, P. K. Constitutively active Rheb induces oncogenic transformation. Oncogene 27, 5729–5740 (2008).

    Article  CAS  Google Scholar 

  16. Santama, N. et al. KIF2β, a new kinesin superfamily protein in non-neuronal cells, is associated with lysosomes and may be implicated in their centrifugal translocation. EMBO J. 17, 5855–5867 (1998).

    Article  CAS  Google Scholar 

  17. Matsushita, M., Tanaka, S., Nakamura, N., Inoue, H. & Kanazawa, H. A novel kinesin-like protein, KIF1Bβ3 is involved in the movement of lysosomes to the cell periphery in non-neuronal cells. Traffic 5, 140–151 (2004).

    Article  CAS  Google Scholar 

  18. Bagshaw, R. D., Callahan, J. W. & Mahuran, D. J. The Arf-family protein, Arl8b, is involved in the spatial distribution of lysosomes. Biochem. Biophys. Res. Commun. 344, 1186–1191 (2006).

    Article  CAS  Google Scholar 

  19. Hofmann, I. & Munro, S. An N-terminally acetylated Arf-like GTPase is localised to lysosomes and affects their motility. J. Cell Sci. 119, 1494–1503 (2006).

    Article  CAS  Google Scholar 

  20. Okai, T. et al. Novel small GTPase subfamily capable of associating with tubulin is required for chromosome segregation. J. Cell Sci. 117, 4705–4715 (2004).

    Article  CAS  Google Scholar 

  21. 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 

  22. Tanida, I., Minematsu-Ikeguchi, N., Ueno, T. & Kominami, E. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 1, 84–91 (2005).

    Article  CAS  Google Scholar 

  23. Ravikumar, B., Duden, R. & Rubinsztein, D. C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117 (2002).

    CAS  PubMed  Google Scholar 

  24. Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N. & Rubinsztein, D. C. α-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009–25013 (2003).

    Article  CAS  Google Scholar 

  25. Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).

    Article  CAS  Google Scholar 

  26. Singh, S. B., Davis, A. S., Taylor, G. A. & Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438–1441 (2006).

    Article  CAS  Google Scholar 

  27. Merlot, S. & Firtel, R. A. Leading the way: directional sensing through phosphatidylinositol 3-kinase and other signaling pathways. J. Cell Sci. 116, 3471–3478 (2003).

    Article  CAS  Google Scholar 

  28. Mohamed, M. M. & Sloane, B. F. Cysteine cathepsins: multifunctional enzymes in cancer. Nat. Rev. Cancer 6, 764–775 (2006).

    Article  CAS  Google Scholar 

  29. Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

    Article  CAS  Google Scholar 

  30. Noda, Y., Sato-Yoshitake, R., Kondo, S., Nangaku, M. & Hirokawa, N. KIF2 is a new microtubule-based anterograde motor that transports membranous organelles distinct from those carried by kinesin heavy chain or KIF3A/B. J. Cell Biol. 129, 157–167 (1995).

    Article  CAS  Google Scholar 

  31. Berger, Z. et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433–442 (2006).

    Article  CAS  Google Scholar 

  32. Narain, Y., Wyttenbach, A., Rankin, J., Furlong, R. A. & Rubinsztein, D. C. A molecular investigation of true dominance in Huntington’s disease. J. Med. Genet. 36, 739–746 (1999).

    Article  CAS  Google Scholar 

  33. Sarkar, S. et al. A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum. Mol. Genet. 17, 170–178 (2008).

    Article  CAS  Google Scholar 

  34. Schlisio, S. et al. The kinesin KIF1Bβ acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 22, 884–893 (2008).

    Article  CAS  Google Scholar 

  35. Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).

    Article  CAS  Google Scholar 

  36. Pryor, P. R., Reimann, F., Gribble, F. M. & Luzio, J. P. Mucolipin-1 is a lysosomal membrane protein required for intracellular lactosylceramide traffic. Traffic 7, 1388–1398 (2006).

    Article  CAS  Google Scholar 

  37. Zhou, X. et al. Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy. Proc. Natl Acad. Sci. USA 106, 8923–8928 (2009).

    Article  CAS  Google Scholar 

  38. Korolchuk, V. I., Mansilla, A., Menzies, F. M. & Rubinsztein, D. C. Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol. Cell 33, 517–527 (2009).

    Article  CAS  Google Scholar 

  39. Tafani, M. et al. Regulation of intracellular pH mediates Bax activation in HeLa cells treated with staurosporine or tumor necrosis factor-α. J. Biol. Chem. 277, 49569–49576 (2002).

    Article  CAS  Google Scholar 

  40. Ong, V. et al. A role for altered microtubule polymer levels in vincristine resistance of childhood acute lymphoblastic leukemia xenografts. J. Pharmacol. Exp. Ther. 324, 434–442 (2008).

    Article  CAS  Google Scholar 

  41. Sarkar, S., Korolchuk, V., Renna, M., Winslow, A. & Rubinsztein, D. C. Methodological considerations for assessing autophagy modulators: a study with calcium phosphate precipitates. Autophagy 5, 307–313 (2009).

    Article  CAS  Google Scholar 

  42. Ryder, E. et al. The DrosDel collection: a set of P-element insertions for generating custom chromosomal aberrations in Drosophila melanogaster. Genetics 167, 797–813 (2004).

    Article  CAS  Google Scholar 

  43. Thibault, S. T. et al. A complementary transposon tool kit for Drosophila melanogaster using P and piggyBac. Nat. Genet. 36, 283–287 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Munro (Medical Research Council, Laboratory of Molecular Biology, Cambridge; ARL8 constructs and antibody), T. Katada (University of Tokyo; anti-ARL8 antibody), W. G. Kaelin (Harvard Medical School; KIF1Bβ), N. Hirokawa (University of Tokyo; KIF2), D. M. Sabatini (Massachusetts Institute of Technology; mTOR, raptor, rictor), T. Yoshimori (Osaka University; eGFP–LC3, mRFP–GFP–LC3), N. Mizushima (Tokyo Medical and Dental University; Atg5-deficient and wild-type Atg5 mouse embryonic fibroblast cell lines), W. J. Strittmatter (Duke University; Q81–eGFP), J. P. Luzio (University of Cambridge; lgp120–eGFP), A. Tolkovsky (University of Cambridge; GFP–LC3 cells), R. Tsien (University of California at San Diego; mCherry), T. Kouno (Toyama Medical and Pharmaceutical University; hLC3B) and K-L. Guan (University of California at San Diego; Rheb); B. Ravikumar, S. Luo and B. Underwood (University of Cambridge) for suggestions, M. Gratian and M. Bowen (University of Cambridge) for microscopy assistance, and the Bloomington Drosophila Stock Center. We are grateful for financial support from a Hughes Hall Research Fellowship (V.I.K. and S. Sarkar), a 2005 Pergolide Fellowship from Eli Lilly Japan (S. Saiki), the British Council Japan Association (S. Saiki), MRC studentships (M.L. and L.J.), a Daphne Jackson Trust Fellowship funded by the MRC (F.H.S.), a Heiser Foundation Postdoctoral Fellowship in Tuberculosis and Leprosy Research (E.A.R.), NIH grant AI069345, and in part NIH grants AI045148 and AI042999 (V.D.), a Wellcome Trust Senior Fellowship in Clinical Science (D.C.R.), an MRC programme grant (D.C.R., C.J.O’K.) and an EU Framework VI (EUROSCA) grant (D.C.R.).

Author information

Author notes

  1. Viktor I. Korolchuk and Shinji Saiki: Joint first authors

  2. Maike Lichtenberg and Farah H. Siddiqi: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Medical Genetics, Cambridge Institute for Medical Genetics, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, UK

    Viktor I. Korolchuk, Shinji Saiki, Maike Lichtenberg, Farah H. Siddiqi, Sara Imarisio, Luca Jahreiss, Sovan Sarkar, Marie Futter, Fiona M. Menzies & David C. Rubinsztein

  2. Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, 87131, USA

    Esteban A. Roberts & Vojo Deretic

  3. Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, UK

    Sara Imarisio & Cahir J. O’Kane

  4. Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, 87131, USA

    Vojo Deretic

Authors
  1. Viktor I. Korolchuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shinji Saiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maike Lichtenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Farah H. Siddiqi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Esteban A. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sara Imarisio
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Luca Jahreiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sovan Sarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marie Futter
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fiona M. Menzies
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Cahir J. O’Kane
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Vojo Deretic
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. David C. Rubinsztein
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors designed and analysed experiments. V.I.K., S. Saiki, M.L., F.H.S., E.A.R., S.I., L.J., S. Sarkar, M.F. and F.M.M. carried out experiments. V.I.K. and D.C.R. wrote the manuscript. D.C.R. supervised the project.

Corresponding author

Correspondence to David C. Rubinsztein.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1363 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Korolchuk, V., Saiki, S., Lichtenberg, M. et al. Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol 13, 453–460 (2011). https://doi.org/10.1038/ncb2204

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2204

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing