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Lysosomal positioning coordinates cellular nutrient responses

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

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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.

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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.

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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.).

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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

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  1. Viktor I. Korolchuk
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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.

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Correspondence to David C. Rubinsztein.

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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

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