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.

  • Review Article
  • Published:

The lysosome as a cellular centre for signalling, metabolism and quality control

Nature Cell Biology volume 21, pages 133–142 (2019)Cite this article

Subjects

Abstract

Long known as terminal degradation stations, lysosomes have emerged as sophisticated signalling centres that govern cell growth, division and differentiation. Lysosomes interface physically and functionally with other organelles, and the master regulator mechanistic target of rapamycin complex 1 kinase is activated on lysosomes in response to nutrient and growth factor inputs. Lysosomes also enable autophagy, a ‘self-eating’ process essential for quality control and stress adaptation. Faulty execution of lysosomal growth and catabolic programmes drives cancer, neurodegeneration and age-related diseases.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Lysosome cell biology.
Fig. 2: Regulation of mTORC1 in response to nutrients in mammalian cells.
Fig. 3: Lysosome-dependent regulation of cellular physiology in response to nutrients.
Fig. 4: Overview of lysosomal roles in neurodegenerative disease and cancer.

Similar content being viewed by others

References

  1. Perera, R. M. & Zoncu, R. The lysosome as a regulatory hub. Annu. Rev. Cell Dev. Biol. 32, 223–253 (2016).

    CAS  PubMed  Google Scholar 

  2. Settembre, C., Fraldi, A., Medina, D. L. & Ballabio, A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14, 283–296 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhao, J., Benlekbir, S. & Rubinstein, J. L. Electron cryomicroscopy observation of rotational states in a eukaryotic V-ATPase. Nature 521, 241–245 (2015).

    CAS  PubMed  Google Scholar 

  4. Jezegou, A. et al. Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy. Proc. Natl Acad. Sci. USA 109, E3434–E3443 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Liu, B., Du, H., Rutkowski, R., Gartner, A. & Wang, X. LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. Science 337, 351–354 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Rong, Y. et al. Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. Proc. Natl Acad. Sci. USA 108, 7826–7831 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Sagne, C. et al. Identification and characterization of a lysosomal transporter for small neutral amino acids. Proc. Natl Acad. Sci. USA 98, 7206–7211 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Wyant, G. A. et al. mTORC1 activator SLC38A9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient. Cell 171, 642–654.e12 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Verdon, Q. et al. SNAT7 is the primary lysosomal glutamine exporter required for extracellular protein-dependent growth of cancer cells. Proc. Natl Acad. Sci. USA 114, E3602–E3611 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Abu-Re-maileh, M. et al. Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science 358, 807–813 (2017).

    CAS  Google Scholar 

  11. Li, S. C. & Kane, P. M. The yeast lysosome-like vacuole: endpoint and crossroads. Biochim. Biophys. Acta 1793, 650–663 (2009).

    CAS  PubMed  Google Scholar 

  12. Russnak, R., Konczal, D. & McIntire, S. L. A family of yeast proteins mediating bidirectional vacuolar amino acid transport. J. Biol. Chem. 276, 23849–23857 (2001).

    CAS  PubMed  Google Scholar 

  13. Polishchuk, E. V. et al. Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis. Dev. Cell 29, 686–700 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. Pu, J. et al. BORC, a multisubunit complex that regulates lysosome positioning. Dev. Cell 33, 176–188 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Li, X. et al. A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation. Nat. Cell Biol. 18, 404–417 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Filipek, P. A. et al. LAMTOR/Ragulator is a negative regulator of Arl8b- and BORC-dependent late endosomal positioning. J. Cell Biol. 216, 4199–4215 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Pu, J., Keren-Kaplan, T. & Bonifacino, J. S. A Ragulator–BORC interaction controls lysosome positioning in response to amino acid availability. J. Cell Biol. 216, 4183–4197 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Rocha, N. et al. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7–RILP–p150 Glued and late endosome positioning. J. Cell Biol. 185, 1209–1225 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Itakura, E., Kishi-Itakura, C. & Mizushima, N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151, 1256–1269 (2012).

    CAS  PubMed  Google Scholar 

  21. Reddy, A., Caler, E. V. & Andrews, N. W. Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Cell 106, 157–169 (2001).

    CAS  PubMed  Google Scholar 

  22. Medina, D. L. et al. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev. Cell 21, 421–430 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Rowland, A. A., Chitwood, P. J., Phillips, M. J. & Voeltz, G. K. ER contact sites define the position and timing of endosome fission. Cell 159, 1027–1041 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wong, Y. C., Ysselstein, D. & Krainc, D. Mitochondria–lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature 554, 382–386 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Elbaz-Alon, Y. et al. A dynamic interface between vacuoles and mitochondria in yeast. Dev. Cell 30, 95–102 (2014).

    CAS  PubMed  Google Scholar 

  26. Gonzalez Montoro, A. et al. Vps39 interacts with Tom40 to establish one of two functionally distinct vacuole–mitochondria contact sites. Dev. Cell 45, 621–636.e7 (2018).

    CAS  PubMed  Google Scholar 

  27. Murley, A. et al. Ltc1 is an ER-localized sterol transporter and a component of ER–mitochondria and ER–vacuole contacts. J. Cell Biol. 209, 539–548 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Thelen, A. M. & Zoncu, R. Emerging roles for the lysosome in lipid metabolism. Trends Cell Biol. 27, 833–850 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wilhelm, L. P. et al. STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites. EMBO J. 36, 1412–1433 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mesmin, B. et al. A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER–Golgi tether OSBP. Cell 155, 830–843 (2013).

    CAS  PubMed  Google Scholar 

  31. Honscher, C. et al. Cellular metabolism regulates contact sites between vacuoles and mitochondria. Dev. Cell 30, 86–94 (2014).

    PubMed  Google Scholar 

  32. Kumar, N. et al. VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites. J. Cell Biol. 217, 3625–3639 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 169, 361–371 (2017).

    CAS  PubMed  Google Scholar 

  36. Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334, 678–683 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Binda, M. et al. The Vam6 GEF controls TORC1 by activating the EGO complex. Mol. Cell 35, 563–573 (2009).

    CAS  PubMed  Google Scholar 

  38. Dubouloz, F., Deloche, O., Wanke, V., Cameroni, E. & De Virgilio, C. The TOR and EGO protein complexes orchestrate microautophagy in yeast. Mol. Cell 19, 15–26 (2005).

    CAS  PubMed  Google Scholar 

  39. Lawrence, R. E. et al. A nutrient-induced affinity switch controls mTORC1 activation by its Rag GTPase–Ragulator lysosomal scaffold. Nat. Cell Biol. 20, 1052–1063 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang, H. et al. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 552, 368–373 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Bar-Peled, L. et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100–1106 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Panchaud, N., Peli-Gulli, M. P. & De Virgilio, C. Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci. Signal. 6, ra42 (2013).

    PubMed  Google Scholar 

  44. Peng, M., Yin, N. & Li, M. O. SZT2 dictates GATOR control of mTORC1 signalling. Nature 543, 433–437 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wolfson, R. L. et al. KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543, 438–442 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Dokudovskaya, S. et al. A conserved coatomer-related complex containing Sec13 and Seh1 dynamically associates with the vacuole in Saccharomyces cerevisiae. Mol. Cell. Proteomics 10, M110.006478 (2011).

    PubMed  PubMed Central  Google Scholar 

  47. Petit, C. S., Roczniak-Ferguson, A. & Ferguson, S. M. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J. Cell Biol. 202, 1107–1122 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Tsun, Z. Y. et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol. Cell 52, 495–505 (2013).

    CAS  PubMed  Google Scholar 

  49. Meng, J. & Ferguson, S. M. GATOR1-dependent recruitment of FLCN–FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids. J. Cell Biol. 217, 2765–2776 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Peli-Gulli, M. P., Raucci, S., Hu, Z., Dengjel, J. & De Virgilio, C. Feedback inhibition of the Rag GTPase GAP complex Lst4–Lst7 safeguards TORC1 from hyperactivation by amino acid signals. Cell Rep. 20, 281–288 (2017).

    CAS  PubMed  Google Scholar 

  51. Peli-Gulli, M. P., Sardu, A., Panchaud, N., Raucci, S. & De Virgilio, C. Amino acids stimulate TORC1 through Lst4–Lst7, a GTPase-activating protein complex for the Rag family GTPase Gtr2. Cell Rep. 13, 1–7 (2015).

    CAS  PubMed  Google Scholar 

  52. Chantranupong, L. et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165, 153–164 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Gu, X. et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358, 813–818 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Wolfson, R. L. et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351, 43–48 (2016).

    CAS  PubMed  Google Scholar 

  55. Kim, J. & Guan, K.-L. mTOR as a central hub of nutrient signaling and cell growth. Nat. Cell Biol. (2019).

  56. Grandison, R. C., Piper, M. D. & Partridge, L. Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 462, 1061–1064 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Rebsamen, M. et al. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature 519, 477–481 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Wang, S. et al. Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347, 188–194 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Efeyan, A. et al. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 493, 679–683 (2013).

    CAS  PubMed  Google Scholar 

  60. Zhang, C. S. et al. The lysosomal v-ATPase–Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab. 20, 526–540 (2014).

    CAS  PubMed  Google Scholar 

  61. Castellano, B. M. et al. Lysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex. Science 355, 1306–1311 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Bar-Peled, L., Schweitzer, L. D., Zoncu, R. & Sabatini, D. M. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150, 1196–1208 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Shen, K. & Sabatini, D. M. Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms. Proc. Natl Acad. Sci. USA 115, 9545–9550 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Shen, K., Choe, A. & Sabatini, D. M. Intersubunit crosstalk in the Rag GTPase heterodimer enables mTORC1 to respond rapidly to amino acid availability. Mol. Cell 68, 552–565.e8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. de Araujo, M. E. G. et al. Crystal structure of the human lysosomal mTORC1 scaffold complex and its impact on signaling. Science 358, 377–381 (2017).

    PubMed  Google Scholar 

  66. Su, M. Y. et al. Hybrid structure of the RagA/C–Ragulator mTORC1 activation complex. Mol. Cell 68, 835–846.e3 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Manifava, M. et al. Dynamics of mTORC1 activation in response to amino acids. eLife 5, e19960 (2016).

    PubMed  PubMed Central  Google Scholar 

  68. Kira, S. et al. Dynamic relocation of the TORC1–Gtr1/2–Ego1/2/3 complex is regulated by Gtr1 and Gtr2. Mol. Biol. Cell 27, 382–396 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Prouteau, M. et al. TORC1 organized in inhibited domains (TOROIDs) regulate TORC1 activity. Nature 550, 265–269 (2017).

    PubMed  PubMed Central  Google Scholar 

  70. Jewell, J. L. et al. Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science 347, 194–198 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Wyant, G. A. et al. NUFIP1 is a ribosome receptor for starvation-induced ribophagy. Science 360, 751–758 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Chapel, A. et al. An extended proteome map of the lysosomal membrane reveals novel potential transporters. Mol. Cell. Proteomics 12, 1572–1588 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Schroder, B. et al. Integral and associated lysosomal membrane proteins. Traffic 8, 1676–1686 (2007).

    PubMed  Google Scholar 

  74. Mancias, J. D., Wang, X., Gygi, S. P., Harper, J. W. & Kimmelman, A. C. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509, 105–109 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhou, X. et al. Dynamic visualization of mTORC1 activity in living cells. Cell Rep. 10, 1767–1777 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).

    PubMed  PubMed Central  Google Scholar 

  77. Porstmann, T. et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Ben-Sahra, I., Howell, J. J., Asara, J. M. & Manning, B. D. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339, 1323–1328 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Robitaille, A. M. et al. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339, 1320–1323 (2013).

    CAS  PubMed  Google Scholar 

  80. Jastrzebski, K., Hannan, K. M., Tchoubrieva, E. B., Hannan, R. D. & Pearson, R. B. Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors 25, 209–226 (2007).

    CAS  PubMed  Google Scholar 

  81. Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Okosun, J. et al. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nat. Genet. 48, 183–188 (2016).

    CAS  PubMed  Google Scholar 

  84. Grabiner, B. C. et al. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 4, 554–563 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Shen, H. M. & Mizushima, N. At the end of the autophagic road: an emerging understanding of lysosomal functions in autophagy. Trends Biochem. Sci. 39, 61–71 (2014).

    CAS  PubMed  Google Scholar 

  86. Owen, J. L. et al. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc. Natl Acad. Sci. USA 109, 16184–16189 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Chen, C., Liu, Y., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009).

    PubMed  PubMed Central  Google Scholar 

  88. Castilho, R. M., Squarize, C. H., Chodosh, L. A., Williams, B. O. & Gutkind, J. S. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell 5, 279–289 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).

    CAS  PubMed  Google Scholar 

  90. Ho, T. T. et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature 543, 205–210 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Leeman, D. S. et al. Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 359, 1277–1283 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Bjedov, I. & Partridge, L. A longer and healthier life with TOR down-regulation: genetics and drugs. Biochem. Soc. Trans. 39, 460–465 (2011).

    CAS  PubMed  Google Scholar 

  93. Kapahi, P. et al. With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab. 11, 453–465 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Ballabio, A. & Gieselmann, V. Lysosomal disorders: from storage to cellular damage. Biochim. Biophys. Acta 1793, 684–696 (2009).

    CAS  PubMed  Google Scholar 

  95. Nixon, R. A. The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983–997 (2013).

    CAS  PubMed  Google Scholar 

  96. Sharma, J., di Ronza, A., Lotfi, P. & Sardiello, M. Lysosomes and brain health. Annu. Rev. Neurosci. 41, 255–276 (2018).

    CAS  PubMed  Google Scholar 

  97. Perera, R. M. & Bardeesy, N. Pancreatic cancer metabolism: breaking it down to build it back up. Cancer Discov. 5, 1247–1261 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. White, E. The role for autophagy in cancer. J. Clin. Invest. 125, 42–46 (2015).

    PubMed  PubMed Central  Google Scholar 

  99. Lie, P. P. Y. & Nixon, R. A. Lysosome trafficking and signaling in health and neurodegenerative diseases. Neurobiol. Dis.. https://doi.org/10.1016/j.nbd.2018.05.015 (2018).

  100. Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    CAS  PubMed  Google Scholar 

  101. Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).

    CAS  PubMed  Google Scholar 

  102. Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. & Sulzer, D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004).

    CAS  PubMed  Google Scholar 

  103. Ebrahimi-Fakhari, D. et al. Distinct roles in vivo for the ubiquitin–proteasome system and the autophagy–lysosomal pathway in the degradation of α-synuclein. J. Neurosci. 31, 14508–14520 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Winslow, A. R. et al. α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J. Cell Biol. 190, 1023–1037 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Decressac, M. et al. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc. Natl Acad. Sci. USA 110, E1817–E1826 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Steger, M. et al. Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. eLife 6, e31012 (2017).

    PubMed  PubMed Central  Google Scholar 

  107. MacLeod, D. A. et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron 77, 425–439 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Nixon, R. A. Amyloid precursor protein and endosomal–lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729–2743 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Cataldo, A. M. et al. App gene dosage modulates endosomal abnormalities of Alzheimer’s disease in a segmental trisomy 16 mouse model of down syndrome. J. Neurosci. 23, 6788–6792 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Jung, J. et al. Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator. eLife 6, e23063 (2017).

    PubMed  PubMed Central  Google Scholar 

  111. Webster, C. P. et al. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 35, 1656–1676 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Amick, J., Roczniak-Ferguson, A. & Ferguson, S. M. C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Mol. Biol. Cell 27, 3040–3051 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ji, Y. J., Ugolino, J., Brady, N. R., Hamacher-Brady, A. & Wang, J. Systemic deregulation of autophagy upon loss of ALS- and FTD-linked C9orf72. Autophagy 13, 1254–1255 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Corrionero, A. & Horvitz, H. R. A C9orf72 ALS/FTD ortholog acts in endolysosomal degradation and lysosomal homeostasis. Curr. Biol. 28, 1522–1535.e5 (2018).

    CAS  PubMed  Google Scholar 

  115. Sellier, C. et al. Loss of C9ORF72 impairs autophagy and synergizes with polyQ ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J. 35, 1276–1297 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Klein, Z. A. et al. Loss of TMEM106B ameliorates lysosomal and frontotemporal dementia-related phenotypes in progranulin-deficient mice. Neuron 95, 281–296.e6 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Mc Donald, J. M. & Krainc, D. Lysosomal proteins as a therapeutic target in neurodegeneration. Annu. Rev. Med. 68, 445–458 (2017).

    Google Scholar 

  118. Hamalisto, S. & Jaattela, M. Lysosomes in cancer—living on the edge (of the cell). Curr. Opin. Cell Biol. 39, 69–76 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Guo, J. Y. et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25, 460–470 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Perera, R. M. et al. Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism. Nature 524, 361–365 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Davidson, S. M. et al. Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat. Med. 23, 235–241 (2017).

    CAS  PubMed  Google Scholar 

  124. Strohecker, A. M. et al. Autophagy sustains mitochondrial glutamine metabolism and growth of Braf V600E-driven lung tumors. Cancer Discov. 3, 1272–1285 (2013).

    CAS  PubMed  Google Scholar 

  125. Calcagni, A. et al. Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling. eLife 5, e17047 (2016).

    PubMed  PubMed Central  Google Scholar 

  126. Di Malta, C. et al. Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. Science 356, 1188–1192 (2017).

    PubMed  PubMed Central  Google Scholar 

  127. Piao, S. & Amaravadi, R. K. Targeting the lysosome in cancer. Ann. N. Y. Acad. Sci. 1371, 45–54 (2015).

    PubMed  PubMed Central  Google Scholar 

  128. McAfee, Q. et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc. Natl Acad. Sci. USA 109, 8253–8258 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Rebecca, V. W. et al. A unified approach to targeting the lysosome’s degradative and growth signaling roles. Cancer Discov. 7, 1266–1283 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Majer, O., Liu, B. & Barton, G. M. Nucleic acid-sensing TLRs: trafficking and regulation. Curr. Opin. Immunol. 44, 26–33 (2017).

    CAS  PubMed  Google Scholar 

  131. Folick, A. et al. Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans. Science 347, 83–86 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Demontis, F. & Perrimon, N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 143, 813–825 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Rodriguez-Navarro, J. A. et al. Inhibitory effect of dietary lipids on chaperone-mediated autophagy. Proc. Natl Acad. Sci. USA 109, E705–E714 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Palmieri, M. et al. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum. Mol. Genet. 20, 3852–3866 (2011).

    CAS  PubMed  Google Scholar 

  135. Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009).

    CAS  PubMed  Google Scholar 

  136. Settembre, C. et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31, 1095–1108 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Martina, J. A., Chen, Y., Gucek, M. & Puertollano, R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8, 903–914 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Roczniak-Ferguson, A. et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 5, ra42 (2012).

    PubMed  PubMed Central  Google Scholar 

  139. Medina, D. L. et al. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat. Cell Biol. 17, 288–299 (2015).

    PubMed  PubMed Central  Google Scholar 

  140. Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Settembre, C. et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15, 647–658 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. O’Rourke, E. J. & Ruvkun, G. MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat. Cell Biol. 15, 668–676 (2013).

    PubMed  PubMed Central  Google Scholar 

  143. Seok, S. et al. Transcriptional regulation of autophagy by an FXR–CREB axis. Nature 516, 108–111 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Lee, J. M. et al. Nutrient-sensing nuclear receptors coordinate autophagy. Nature 516, 112–115 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  146. Sarkar, S. et al. Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat. Chem. Biol. 3, 331–338 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Tain, L. S. et al. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat. Neurosci. 12, 1129–1135 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Malagelada, C., Jin, Z. H., Jackson-Lewis, V., Przedborski, S. & Greene, L. A. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J. Neurosci. 30, 1166–1175 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Menzies, F. M. et al. Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133, 93–104 (2010).

    PubMed  Google Scholar 

  150. Zhang, X. et al. Rapamycin treatment augments motor neuron degeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis. Autophagy 7, 412–425 (2011).

    CAS  PubMed  Google Scholar 

  151. Domanskyi, A. et al. Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson’s disease models. FASEB J. 25, 2898–2910 (2011).

    CAS  PubMed  Google Scholar 

  152. Kang, S. A. et al. mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science 341, 1236566 (2013).

    PubMed  PubMed Central  Google Scholar 

  153. Thoreen, C. C. et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023–8032 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Fan, Q. W. et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9, 341–349 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Nezich, C. L., Wang, C., Fogel, A. I. & Youle, R. J. MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5. J. Cell Biol. 210, 435–450 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Martina, J. A., Diab, H. I., Brady, O. A. & Puertollano, R. TFEB and TFE3 are novel components of the integrated stress response. EMBO J. 35, 479–495 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Santaguida, S. & Amon, A. Aneuploidy triggers a TFEB-mediated lysosomal stress response. Autophagy 11, 2383–2384 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Polito, V. A. et al. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol. Med. 6, 1142–1160 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Xiao, Q. et al. Neuronal-targeted TFEB accelerates lysosomal degradation of APP, reducing Aβ generation and amyloid plaque pathogenesis. J. Neurosci. 35, 12137–12151 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Tsunemi, T. et al. PGC-1α rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci. Transl Med. 4, 142ra197 (2012).

    Google Scholar 

Download references

Acknowledgements

We thank all members of the Zoncu Lab for helpful insights. This work was supported by the NIH Director’s New Innovator Award (1DP2CA195761-01), the Pew-Stewart Scholarship for Cancer Research, the Damon Runyon-Rachleff Innovation Award, the Edward Mallinckrodt, Jr Foundation Grant and the Packer Wentz Endowment to R.Z., and a National Science Foundation Graduate Research Fellowship (DGE 1106400) to R.E.L.

Author information

Authors and Affiliations

  1. Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA

    Rosalie E. Lawrence & Roberto Zoncu

  2. The Paul F. Glenn Center for Aging Research, University of California at Berkeley, Berkeley, CA, USA

    Rosalie E. Lawrence & Roberto Zoncu

Authors
  1. Rosalie E. Lawrence
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberto Zoncu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.Z. is co-founder and stockholder in Frontier Medicines Corp.

Corresponding author

Correspondence to Roberto Zoncu.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lawrence, R.E., Zoncu, R. The lysosome as a cellular centre for signalling, metabolism and quality control. Nat Cell Biol 21, 133–142 (2019). https://doi.org/10.1038/s41556-018-0244-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41556-018-0244-7

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