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.

Signals from the lysosome: a control centre for cellular clearance and energy metabolism

Key Points

  • Lysosomes are cellular organelles involved in the degradation and recycling of cellular waste. Extracellular and intracellular materials to be degraded reach the lysosome via endocytosis and autophagy, respectively. Lysosomes are also involved in secretion and plasma membrane repair, by fusing to the plasma membrane in a process termed lysosomal exocytosis.

  • Lysosomal function is performed by lumenal hydrolases that are responsible for substrate digestion and by membrane-associated proteins that handle trafficking of materials into and out of the lysosome.

  • A complex machinery, which includes the kinase complex mammalian target of rapamycin complex 1 (mTORC1, a major regulator of cell growth), the vesicular ATPase complex and additional complexes, is located on the lysosomal surface and is devoted to sensing the nutrient content of the lysosome. This complex is called the lysosomal nutrient sensing (LYNUS) machinery.

  • Most genes encoding lysosomal proteins belong to a gene network termed CLEAR (coordinated lysosomal expression and regulation), and they are transcriptionally regulated by transcription factor EB (TFEB), the master regulator for lysosomal biogenesis. Using this regulatory mechanism, cells can adapt lysosomal function to respond to environmental cues.

  • The activity of TFEB is induced following starvation, by both transcriptional autoregulation and a phosphorylation-dependent mechanism. Once activated, TFEB mediates the starvation response by activating lipid catabolism via the regulation of the master lipid metabolism genes PPARα (peroxisome proliferator-activated receptor-α) and PGC1α (PPARγ co-activator 1α). TFEB regulation and function are conserved in worms.

  • Lysosomal and autophagy dysfunction occurs both in lysosomal storage diseases (LSDs) and in common neurodegenerative diseases, resulting in defective cellular clearance and the accumulation of toxic material. Thus, TFEB-mediated induction of cellular clearance may represent an attractive therapeutic strategy for these disorders.

Abstract

For a long time, lysosomes were considered merely to be cellular 'incinerators' involved in the degradation and recycling of cellular waste. However, now there is compelling evidence indicating that lysosomes have a much broader function and that they are involved in fundamental processes such as secretion, plasma membrane repair, signalling and energy metabolism. Furthermore, the essential role of lysosomes in autophagic pathways puts these organelles at the crossroads of several cellular processes, with significant implications for health and disease. The identification of a master regulator, transcription factor EB (TFEB), that regulates lysosomal biogenesis and autophagy has revealed how the lysosome adapts to environmental cues, such as starvation, and targeting TFEB may provide a novel therapeutic strategy for modulating lysosomal function in human disease.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Main functions of the lysosome and their relationship with key cellular processes.
Figure 2: Model of TFEB regulation and function during starvation.
Figure 3: Defective cellular clearance in neurodegenerative diseases.
Figure 4: TFEB regulates cellular clearance.

References

  1. de Duve, C. The lysosome turns fifty. Nature Cell Biol. 7, 847–849 (2005).

    CAS  PubMed  Google Scholar 

  2. Saftig, P. & Klumperman, J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nature Rev. Mol. Cell Biol. 10, 623–635 (2009). A comprehensive overview of lysosomal function and the role of lysosomal membrane proteins.

    Article  CAS  Google Scholar 

  3. Luzio, J. P., Parkinson, M. D., Gray, S. R. & Bright, N. A. The delivery of endocytosed cargo to lysosomes. Biochem. Soc. Trans. 37, 1019–1021 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kaushik, S. & Cuervo, A. M. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 22, 407–417 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mijaljica, D., Prescott, M. & Devenish, R. J. Microautophagy in mammalian cells: revisiting a 40-year-old conundrum. Autophagy 7, 673–682 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Chieregatti, E. & Meldolesi, J. Regulated exocytosis: new organelles for non-secretory purposes. Nature Rev. Mol. Cell Biol. 6, 181–187 (2005).

    Article  Google Scholar 

  8. Verhage, M. & Toonen, R. F. Regulated exocytosis: merging ideas on fusing membranes. Curr. Opin. Cell Biol. 19, 402–408 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Blott, E. J. & Griffiths, G. M. Secretory lysosomes. Nature Rev. Mol. Cell Biol. 3, 122–131 (2002).

    Article  CAS  Google Scholar 

  10. Mostov, K. & Werb, Z. Journey across the osteoclast. Science 276, 219–220 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Stinchcombe, J., Bossi, G. & Griffiths, G. M. Linking albinism and immunity: the secrets of secretory lysosomes. Science 305, 55–59 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009). Discovers that lysosomal function is subject to global transcriptional regulation by the master regulator TFEB.

    Article  CAS  PubMed  Google Scholar 

  13. Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011). Shows that the biogenesis of both lysosomes and autophagosomes are jointly regulated by TFEB. Starvation induces TFEB cytoplasm-to-nucleus shuttling via a phosphorylation-dependent mechanism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Braulke, T. & Bonifacino, J. S. Sorting of lysosomal proteins. Biochim. Biophys. Acta 1793, 605–614 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Pfeffer, S. R. Rab GTPases: specifying and deciphering organelle identity and function. Trends Cell Biol. 11, 487–491 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Zerial, M. & McBride, H. Rab proteins as membrane organizers. Nature Rev. Mol. Cell Biol. 2, 107–117 (2001).

    Article  CAS  Google Scholar 

  18. Rink, J., Ghigo, E., Kalaidzidis, Y. & Zerial, M. Rab conversion as a mechanism of progression from early to late endosomes. Cell 122, 735–749 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Henne, W. M., Buchkovich, N. J. & Emr, S. D. The ESCRT pathway. Dev. Cell 21, 77–91 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Luzio, J. P. et al. ESCRT proteins and the regulation of endocytic delivery to lysosomes. Biochem. Soc. Trans. 37, 178–180 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Sridhar, S. et al. The lipid kinase PI4KIIIβ preserves lysosomal identity. EMBO J. 32, 324–339 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Schulze, H., Kolter, T. & Sandhoff, K. Principles of lysosomal membrane degradation: cellular topology and biochemistry of lysosomal lipid degradation. Biochim. Biophys. Acta 1793, 674–683 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Rojas, R. et al. Regulation of retromer recruitment to endosomes by sequential action of Rab5 and Rab7. J. Cell Biol. 183, 513–526 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang, T., Ming, Z., Xiaochun, W. & Hong, W. Rab7: role of its protein interaction cascades in endo-lysosomal traffic. Cell. Signal. 23, 516–521 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Pryor, P. R. et al. Combinatorial SNARE complexes with VAMP7 or VAMP8 define different late endocytic fusion events. EMBO Rep. 5, 590–595 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Weber, T. et al. SNAREpins: minimal machinery for membrane fusion. Cell 92, 759–772 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Jahn, R. & Scheller, R. H. SNAREs — engines for membrane fusion. Nature Rev. Mol. Cell Biol. 7, 631–643 (2006).

    Article  CAS  Google Scholar 

  28. Ohya, T. et al. Reconstitution of Rab- and SNARE-dependent membrane fusion by synthetic endosomes. Nature 459, 1091–1097 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Zeigerer, A. et al. Rab5 is necessary for the biogenesis of the endolysosomal system in vivo. Nature 485, 465–470 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. Hamasaki, M. et al. Autophagosomes form at ER–mitochondria contact sites. Nature 495, 389–393 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Ghosh, P., Dahms, N. M. & Kornfeld, S. Mannose 6-phosphate receptors: new twists in the tale. Nature Rev. Mol. Cell Biol. 4, 202–212 (2003).

    Article  CAS  Google Scholar 

  33. Neufeld, E. F. The uptake of enzymes into lysosomes: an overview. Birth Defects Orig. Artic. Ser. 16, 77–84 (1980).

    CAS  PubMed  Google Scholar 

  34. Reczek, D. et al. LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of β-glucocerebrosidase. Cell 131, 770–783 (2007). Reveals a new transport mechanism of lysosomal enzymes that is responsible for the targeting of β-glucocerebrosidase.

    Article  CAS  PubMed  Google Scholar 

  35. Gallala, H. D., Breiden, B. & Sandhoff, K. Regulation of the NPC2 protein-mediated cholesterol trafficking by membrane lipids. J. Neurochem. 116, 702–707 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Munford, R. S., Sheppard, P. O. & O'Hara, P. J. Saposin-like proteins (SAPLIP) carry out diverse functions on a common backbone structure. J. Lipid Res. 36, 1653–1663 (1995).

    CAS  PubMed  Google Scholar 

  37. Kolter, T. & Sandhoff, K. Principles of lysosomal membrane digestion: stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids. Annu. Rev. Cell Dev. Biol. 21, 81–103 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Furst, W. & Sandhoff, K. Activator proteins and topology of lysosomal sphingolipid catabolism. Biochim. Biophys. Acta 1126, 1–16 (1992).

    Article  CAS  PubMed  Google Scholar 

  39. Mobius, W., Herzog, V., Sandhoff, K. & Schwarzmann, G. Intracellular distribution of a biotin-labeled ganglioside, GM1, by immunoelectron microscopy after endocytosis in fibroblasts. J. Histochem. Cytochem. 47, 1005–1014 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Burkhardt, J. K. et al. Accumulation of sphingolipids in SAP-precursor (prosaposin)-deficient fibroblasts occurs as intralysosomal membrane structures and can be completely reversed by treatment with human SAP-precursor. Eur. J. Cell Biol. 73, 10–18 (1997).

    CAS  PubMed  Google Scholar 

  41. Bradova, V. et al. Prosaposin deficiency: further characterization of the sphingolipid activator protein-deficient sibs. Multiple glycolipid elevations (including lactosylceramidosis), partial enzyme deficiencies and ultrastructure of the skin in this generalized sphingolipid storage disease. Hum. Genet. 92, 143–152 (1993).

    Article  CAS  PubMed  Google Scholar 

  42. Schnabel, D. et al. Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is caused by a mutation in the initiation codon of their common gene. J. Biol. Chem. 267, 3312–3315 (1992).

    CAS  PubMed  Google Scholar 

  43. Cosma, M. P. et al. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell 113, 445–456 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Dierks, T. et al. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human Cα-formylglycine generating enzyme. Cell 113, 435–444 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Bagshaw, R. D., Mahuran, D. J. & Callahan, J. W. Lysosomal membrane proteomics and biogenesis of lysosomes. Mol. Neurobiol. 32, 27–41 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Callahan, J. W., Bagshaw, R. D. & Mahuran, D. J. The integral membrane of lysosomes: its proteins and their roles in disease. J. Proteom. 72, 23–33 (2009).

    Article  CAS  Google Scholar 

  47. Lubke, T., Lobel, P. & Sleat, D. E. Proteomics of the lysosome. Biochim. Biophys. Acta 1793, 625–635 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Schroder, B. A., Wrocklage, C., Hasilik, A. & Saftig, P. The proteome of lysosomes. Proteomics 10, 4053–4076 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Sleat, D. E., Jadot, M. & Lobel, P. Lysosomal proteomics and disease. Proteomics Clin. Appl. 1, 1134–1146 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Conner, S. D. & Schmid, S. L. Regulated portals of entry into the cell. Nature 422, 37–44 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Doherty, G. J. & McMahon, H. T. Mechanisms of endocytosis. Annu. Rev. Biochem. 78, 857–902 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Hansen, C. G. & Nichols, B. J. Molecular mechanisms of clathrin-independent endocytosis. J. Cell Sci. 122, 1713–1721 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sorkin, A. & von Zastrow, M. Endocytosis and signalling: intertwining molecular networks. Nature Rev. Mol. Cell Biol. 10, 609–622 (2009).

    Article  CAS  Google Scholar 

  54. Katzmann, D. J., Babst, M. & Emr, S. D. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 106, 145–155 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Raiborg, C. & Stenmark, H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458, 445–452 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Haglund, K. & Dikic, I. The role of ubiquitylation in receptor endocytosis and endosomal sorting. J. Cell Sci. 125, 265–275 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Ohkuma, S. & Poole, B. Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc. Natl Acad. Sci. USA 75, 3327–3331 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ohkuma, S., Moriyama, Y. & Takano, T. Identification and characterization of a proton pump on lysosomes by fluorescein–isothiocyanate–dextran fluorescence. Proc. Natl Acad. Sci. USA 79, 2758–2762 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Graves, A. R., Curran, P. K., Smith, C. L. & Mindell, J. A. The Cl/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. Nature 453, 788–792 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Kasper, D. et al. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. EMBO J. 24, 1079–1091 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Weinert, S. et al. Lysosomal pathology and osteopetrosis upon loss of H+-driven lysosomal Cl accumulation. Science 328, 1401–1403 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Mindell, J. A. Lysosomal acidification mechanisms. Annu. Rev. Physiol. 74, 69–86 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Zhang, F., Jin, S., Yi, F. & Li, P. L. TRP–ML1 functions as a lysosomal NAADP-sensitive Ca2+ release channel in coronary arterial myocytes. J. Cell. Mol. Med. 13, 3174–3185 (2009).

    Article  PubMed  Google Scholar 

  64. Zhang, F., Xu, M., Han, W. Q. & Li, P. L. Reconstitution of lysosomal NAADP–TRP–ML1 signaling pathway and its function in TRP–ML1−/− cells. Am. J. Physiol. Cell Physiol. 301, C421–C430 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Calcraft, P. J. et al. NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature 459, 596–600 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sahu, R. et al. Microautophagy of cytosolic proteins by late endosomes. Dev. Cell 20, 131–139 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ahlberg, J., Marzella, L. & Glaumann, H. Uptake and degradation of proteins by isolated rat liver lysosomes. Suggestion of a microautophagic pathway of proteolysis. Lab. Invest. 47, 523–532 (1982).

    CAS  PubMed  Google Scholar 

  68. Cuervo, A. M. & Dice, J. F. A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273, 501–503 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Chiang, H. L., Terlecky, S. R., Plant, C. P. & Dice, J. F. A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science 246, 382–385 (1989).

    Article  CAS  PubMed  Google Scholar 

  70. He, C. & Klionsky, D. J. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43, 67–93 (2009). Reviews the complex molecular mechanisms and pathways involved in the regulation of autophagy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ravikumar, B. et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol. Rev. 90, 1383–1435 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Rodriguez, A., Webster, P., Ortego, J. & Andrews, N. W. Lysosomes behave as Ca2+-regulated exocytic vesicles in fibroblasts and epithelial cells. J. Cell Biol. 137, 93–104 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chavez, R. A., Miller, S. G. & Moore, H. P. A biosynthetic regulated secretory pathway in constitutive secretory cells. J. Cell Biol. 133, 1177–1191 (1996).

    Article  CAS  PubMed  Google Scholar 

  74. Coorssen, J. R., Schmitt, H. & Almers, W. Ca2+ triggers massive exocytosis in Chinese hamster ovary cells. EMBO J. 15, 3787–3791 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Stinchcombe, J. C. & Griffiths, G. M. Regulated secretion from hemopoietic cells. J. Cell Biol. 147, 1–6 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Andrews, N. W. Regulated secretion of conventional lysosomes. Trends Cell Biol. 10, 316–321 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Jaiswal, J. K., Andrews, N. W. & Simon, S. M. Membrane proximal lysosomes are the major vesicles responsible for calcium-dependent exocytosis in nonsecretory cells. J. Cell Biol. 159, 625–635 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Stinchcombe, J. C. & Griffiths, G. M. Secretory mechanisms in cell-mediated cytotoxicity. Annu. Rev. Cell Dev. Biol. 23, 495–517 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Logan, M. R., Odemuyiwa, S. O. & Moqbel, R. Understanding exocytosis in immune and inflammatory cells: the molecular basis of mediator secretion. J. Allergy Clin. Immunol. 111, 923–932 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Wesolowski, J. & Paumet, F. The impact of bacterial infection on mast cell degranulation. Immunol. Res. 51, 215–226 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Ren, Q., Ye, S. & Whiteheart, S. W. The platelet release reaction: just when you thought platelet secretion was simple. Curr. Opin. Hematol. 15, 537–541 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Tulsiani, D. R., Abou-Haila, A., Loeser, C. R. & Pereira, B. M. The biological and functional significance of the sperm acrosome and acrosomal enzymes in mammalian fertilization. Exp. Cell Res. 240, 151–164 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Rao, S. K., Huynh, C., Proux-Gillardeaux, V., Galli, T. & Andrews, N. W. Identification of SNAREs involved in synaptotagmin VII-regulated lysosomal exocytosis. J. Biol. Chem. 279, 20471–20479 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Bossi, G. & Griffiths, G. M. CTL secretory lysosomes: biogenesis and secretion of a harmful organelle. Semin. Immunol. 17, 87–94 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. LaPlante, J. M. et al. Lysosomal exocytosis is impaired in mucolipidosis type IV. Mol. Genet. Metab. 89, 339–348 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Medina, D. L. et al. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev. Cell 21, 421–430 (2011). The first demonstration that TFEB promotes cellular clearance in human disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dong, X. P. et al. Activating mutations of the TRPML1 channel revealed by proline-scanning mutagenesis. J. Biol. Chem. 284, 32040–32052 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  89. DeSelm, C. J. et al. Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev. Cell 21, 966–974 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ganesan, A. K. et al. Genome-wide siRNA-based functional genomics of pigmentation identifies novel genes and pathways that impact melanogenesis in human cells. PLoS Genet. 4, e1000298 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gerasimenko, J. V., Gerasimenko, O. V. & Petersen, O. H. Membrane repair: Ca2+-elicited lysosomal exocytosis. Curr. Biol. 11, R971–R974 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  93. Roy, D. et al. A process for controlling intracellular bacterial infections induced by membrane injury. Science 304, 1515–1518 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Han, R. et al. Dysferlin-mediated membrane repair protects the heart from stress-induced left ventricular injury. J. Clin. Invest. 117, 1805–1813 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ferron, M. et al. A RANKL–PKCβ–TFEB signaling cascade is necessary for lysosomal biogenesis in osteoclasts. Genes Dev. (in the press) (doi:10.1101/gad.213827.113).

  96. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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  PubMed  PubMed Central  Google Scholar 

  98. Efeyan, A. et al. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 493, 679–183 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Ganley, I. G. et al. ULK1·ATG13·FIP200 complex mediates mTOR signaling and is essential for autophagy. J. Biol. Chem. 284, 12297–12305 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1–Atg13–FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Jung, C. H. et al. ULK–Atg13–FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992–2003 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chan, E. Y., Kir, S. & Tooze, S. A. siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy. J. Biol. Chem. 282, 25464–25474 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Hara, T. et al. FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J. Cell Biol. 181, 497–510 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  104. 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). Identifies an amino acid sensing machinery that is located on the lysosomal surface and involves mTORC1. This implicates the lysosome in signalling and cellular energy metabolism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cang, C. et al. mTOR regulates lysosomal ATP-sensitive two-pore Na+ channels to adapt to metabolic state. Cell 152, 778–790 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21–35 (2011).

    Article  CAS  Google Scholar 

  108. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Rong, Y. et al. Clathrin and phosphatidylinositol-4,5-bisphosphate regulate autophagic lysosome reformation. Nature Cell Biol. 14, 924–934 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Rehli, M., Den Elzen, N., Cassady, A. I., Ostrowski, M. C. & Hume, D. A. Cloning and characterization of the murine genes for bHLH-ZIP transcription factors TFEC and TFEB reveal a common gene organization for all MiT subfamily members. Genomics 56, 111–120 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Medendorp, K. et al. Molecular mechanisms underlying the MiT translocation subgroup of renal cell carcinomas. Cytogenet. Genome Res. 118, 157–165 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Ma, X., Godar, R. J., Liu, H. & Diwan, A. Enhancing lysosome biogenesis attenuates BNIP3-induced cardiomyocyte death. Autophagy 8, 297–309 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  115. Cuervo, A. M. Cell biology. Autophagy's top chef. Science 332, 1392–1393 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Ma, D., Panda, S. & Lin, J. D. Temporal orchestration of circadian autophagy rhythm by C/EBPβ. EMBO J. 30, 4642–4651 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Rzymski, T. et al. Regulation of autophagy by ATF4 in response to severe hypoxia. Oncogene 29, 4424–4435 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Rouschop, K. M. et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J. Clin. Invest. 120, 127–141 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. van der Vos, K. E. et al. Modulation of glutamine metabolism by the PI(3)K–PKB–FOXO network regulates autophagy. Nature Cell Biol. 14, 829–837 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhao, J. et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 6, 472–483 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Mammucari, C. et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 6, 458–471 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Chauhan, S. et al. ZKSCAN3 is a master transcriptional repressor of autophagy. Mol. Cell (2013).

  124. Calnan, D. R. & Brunet, A. The FoxO code. Oncogene 27, 2276–2288 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Dephoure, N. et al. A quantitative atlas of mitotic phosphorylation. Proc. Natl Acad. Sci. USA 105, 10762–10767 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Cea, M. et al. Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition. Blood 120, 3519–3529 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Pena-Llopis, S. et al. Regulation of TFEB and V-ATPases by mTORC1. EMBO J. 30, 3242–3258 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Martina, J. A. & Puertollano, R. Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. J. Cell Biol. 200, 475–491 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Settembre, C. et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nature Cell Biol. 21 Apr 2013 (doi:10.1038/ncb2718).

  132. Singh, R. & Cuervo, A. M. Autophagy in the cellular energetic balance. Cell Metab. 13, 495–504 (2011). Shows that lipid droplets are sequestered by autophagosomes for degradation and recycling to generate free fatty acids.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rodriguez-Navarro, J. A. & Cuervo, A. M. Dietary lipids and aging compromise chaperone-mediated autophagy by similar mechanisms. Autophagy 8, 1152–1154 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Rodriguez-Navarro, J. A. et al. Inhibitory effect of dietary lipids on chaperone-mediated autophagy. Proc. Natl Acad. Sci. USA 109, e705–e714 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Yang, L., Li, P., Fu, S., Calay, E. S. & Hotamisligil, G. S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11, 467–478 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Woloszynek, J. C., Coleman, T., Semenkovich, C. F. & Sands, M. S. Lysosomal dysfunction results in altered energy balance. J. Biol. Chem. 282, 35765–35771 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Du, H., Duanmu, M., Witte, D. & Grabowski, G. A. Targeted disruption of the mouse lysosomal acid lipase gene: long-term survival with massive cholesteryl ester and triglyceride storage. Hum. Mol. Genet. 7, 1347–1354 (1998).

    Article  CAS  PubMed  Google Scholar 

  139. Finck, B. N. & Kelly, D. P. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J. Clin. Invest. 116, 615–622 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Grove, C. A. et al. A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors. Cell 138, 314–327 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. O'Rourke, E. J. & Ruvkun, G. MXL-3 and HLH-30 transcriptionally link lysosomal lipolysis and autophagy to nutrient availability. Nature Cell Biol. 21 Apr 2013 (doi:10.1038/ncb2741).

  142. Kaeberlein, T. L. et al. Lifespan extension in Caenorhabditis elegans by complete removal of food. Aging Cell 5, 487–494 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Melendez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Steingrimsson, E., Tessarollo, L., Reid, S. W., Jenkins, N. A. & Copeland, N. G. The bHLH-Zip transcription factor Tfeb is essential for placental vascularization. Development 125, 4607–4616 (1998).

    CAS  PubMed  Google Scholar 

  145. Cuervo, A. M. & Dice, J. F. When lysosomes get old. Exp. Gerontol. 35, 119–131 (2000).

    Article  CAS  PubMed  Google Scholar 

  146. Rubinsztein, D. C., Marino, G. & Kroemer, G. Autophagy and aging. Cell 146, 682–695 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  148. Cox, T. M. & Cachon-Gonzalez, M. B. The cellular pathology of lysosomal diseases. J. Pathol. 226, 241–254 (2012).

    Article  CAS  PubMed  Google Scholar 

  149. Futerman, A. H. & van Meer, G. The cell biology of lysosomal storage disorders. Nature Rev. Mol. Cell Biol. 5, 554–565 (2004).

    Article  CAS  Google Scholar 

  150. Schultz, M. L., Tecedor, L., Chang, M. & Davidson, B. L. Clarifying lysosomal storage diseases. Trends Neurosciences 34, 401–410 (2011).

    Article  CAS  Google Scholar 

  151. Vitner, E. B., Platt, F. M. & Futerman, A. H. Common and uncommon pathogenic cascades in lysosomal storage diseases. J. Biol. Chem. 285, 20423–20427 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Walkley, S. U. Pathogenic cascades in lysosomal disease — why so complex? J. Inherit. Metab. Dis. 32, 181–189 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lieberman, A. P. et al. Autophagy in lysosomal storage disorders. Autophagy 8, 719–730 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. de Pablo-Latorre, R. et al. Impaired parkin-mediated mitochondrial targeting to autophagosomes differentially contributes to tissue pathology in lysosomal storage diseases. Hum. Mol. Genet. 21, 1770–1781 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Di Malta, C., Fryer, J. D., Settembre, C. & Ballabio, A. Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder. Proc. Natl Acad. Sci. USA 109, E2334–E2342 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Fraldi, A. et al. Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders. EMBO J. 29, 3607–3620 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Settembre, C. et al. A block of autophagy in lysosomal storage disorders. Hum. Mol. Genet. 17, 119–129 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. Cox, T. M. in Lysosomal Storage Disorders: A Practical Guide (ed. Atul Mehta, B. W. ) 153–165 (Wiley-Blackwell, 2012).

  159. Wong, E. & Cuervo, A. M. Autophagy gone awry in neurodegenerative diseases. Nature Neurosci. 13, 805–811 (2010).

    Article  CAS  PubMed  Google Scholar 

  160. Harris, H. & Rubinsztein, D. C. Control of autophagy as a therapy for neurodegenerative disease. Nature Rev. Neurol. 8, 108–117 (2012). A comprehensive overview of how the modulation of autophagy can be a promising therapeutic strategy for neurodegenerative diseases.

    Article  CAS  Google Scholar 

  161. Jeong, H. et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137, 60–72 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Orenstein, S. J. et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nature Neurosci. 16, 394–406 (2013).

    Article  CAS  PubMed  Google Scholar 

  165. Martinez-Vicente, M. et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nature Neurosci. 13, 567–576 (2010).

    Article  CAS  PubMed  Google Scholar 

  166. Aharon-Peretz, J., Rosenbaum, H. & Gershoni-Baruch, R. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N. Engl. J. Med. 351, 1972–1977 (2004).

    Article  CAS  PubMed  Google Scholar 

  167. Sidransky, E. et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N. Engl. J. Med. 361, 1651–1661 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Brady, R. O., Kanfer, J. N. & Shapiro, D. Metabolism of glucocerebrosides. II. Evidence of an enzymatic deficiency in Gaucher's disease. Biochem. Biophys. Res. Commun. 18, 221–225 (1965).

    Article  CAS  PubMed  Google Scholar 

  169. Mazzulli, J. R. et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146, 37–52 (2011). Demonstrates how partial deficiency of the lysosomal enzyme β-glucocerebrosidase can be a major predisposing factor in Parkinson's disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Ramirez, A. et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nature Genet. 38, 1184–1191 (2006).

    Article  CAS  PubMed  Google Scholar 

  171. Usenovic, M. & Krainc, D. Lysosomal dysfunction in neurodegeneration: the role of ATP13A2/PARK9. Autophagy 8, 987–988 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Valente, E. M. et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160 (2004).

    Article  CAS  PubMed  Google Scholar 

  173. Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature Cell Biol. 12, 119–131 (2010).

    Article  CAS  PubMed  Google Scholar 

  174. Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

    Article  CAS  PubMed  Google Scholar 

  176. Zimprich, A. et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89, 168–175 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Chartier-Harlin, M. C. et al. Translation initiator EIF4G1 mutations in familial Parkinson disease. Am. J. Hum. Genet. 89, 398–406 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Lee, J. H. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158 (2010). An important example of lysosomal dysfunction associated with Alzheimer's disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Coen, K. et al. Lysosomal calcium homeostasis defects, not proton pump defects, cause endo–lysosomal dysfunction in PSEN-deficient cells. J. Cell Biol. 198, 23–35 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nature Genet. 37, 806–808 (2005).

    Article  CAS  PubMed  Google Scholar 

  181. Verhoeven, K. et al. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot–Marie–Tooth type 2B neuropathy. Am. J. Hum. Genet. 72, 722–727 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Saitsu, H. et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nature Genet. 45, 445–449 (2013).

    Article  CAS  PubMed  Google Scholar 

  183. Yang, D. S. et al. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. Brain 134, 258–277 (2011).

    Article  PubMed  Google Scholar 

  184. Mueller-Steiner, S. et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron 51, 703–714 (2006).

    Article  CAS  PubMed  Google Scholar 

  185. Sun, B. et al. Cystatin C–cathepsin B axis regulates amyloid-β levels and associated neuronal deficits in an animal model of Alzheimer's disease. Neuron 60, 247–257 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. 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  PubMed  Google Scholar 

  187. 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).

    Article  CAS  PubMed  Google Scholar 

  188. Rose, C. et al. Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease. Hum. Mol. Genet. 19, 2144–2153 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Tanaka, M. et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nature Med. 10, 148–154 (2004).

    Article  CAS  PubMed  Google Scholar 

  190. Spampanato, C. et al. Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease. EMBO Mol Med. 11 Apr 2013 (doi:10.1002/emmm.201202176.

  191. Dehay, B. et al. Pathogenic lysosomal depletion in Parkinson's disease. J. Neurosci. 30, 12535–12544 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Tsunemi, T. et al. PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci. Transl. Med. 4, 142ra97 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Pastore, N. et al. Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in α-1-anti-trypsin deficiency. EMBO Mol. Med. 5, 397–412 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Bagshaw, R. D., Mahuran, D. J. & Callahan, J. W. A proteomic analysis of lysosomal integral membrane proteins reveals the diverse composition of the organelle. Mol. Cell. Proteom. 4, 133–143 (2005).

    Article  CAS  Google Scholar 

  195. Kobayashi, T. et al. Separation and characterization of late endosomal membrane domains. J. Biol. Chem. 277, 32157–32164 (2002).

    Article  CAS  PubMed  Google Scholar 

  196. Andrejewski, N. et al. Normal lysosomal morphology and function in LAMP-1-deficient mice. J. Biol. Chem. 274, 12692–12701 (1999).

    Article  CAS  PubMed  Google Scholar 

  197. Nishi, T. & Forgac, M. The vacuolar (H+)-ATPases — nature's most versatile proton pumps. Nature Rev. Mol. Cell Biol. 3, 94–103 (2002).

    Article  CAS  Google Scholar 

  198. Marshansky, V. & Futai, M. The V-type H+-ATPase in vesicular trafficking: targeting, regulation and function. Curr. Opin. Cell Biol. 20, 415–426 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Dong, X. P. et al. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455, 992–996 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Wong, C. O., Li, R., Montell, C. & Venkatachalam, K. Drosophila TRPML is required for TORC1 activation. Curr. Biol. 22, 1616–1621 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Bargal, R. et al. Identification of the gene causing mucolipidosis type IV. Nature Genet. 26, 118–123 (2000).

    Article  CAS  PubMed  Google Scholar 

  202. Bassi, M. T. et al. Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV. Am. J. Hum. Genet. 67, 1110–1120 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Jentsch, T. J., Poet, M., Fuhrmann, J. C. & Zdebik, A. A. Physiological functions of CLC Cl channels gleaned from human genetic disease and mouse models. Annu. Rev. Physiol. 67, 779–807 (2005).

    Article  CAS  PubMed  Google Scholar 

  204. Cuervo, A. M., Gomes, A. V., Barnes, J. A. & Dice, J. F. Selective degradation of annexins by chaperone-mediated autophagy. J. Biol. Chem. 275, 33329–33335 (2000).

    Article  CAS  PubMed  Google Scholar 

  205. Nishino, I. et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406, 906–910 (2000).

    Article  CAS  PubMed  Google Scholar 

  206. Lloyd-Evans, E. et al. Niemann–Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nature Med. 14, 1247–1255 (2008).

    Article  CAS  PubMed  Google Scholar 

  207. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Hrebicek, M. et al. Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome). Am. J. Hum. Genet. 79, 807–819 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Fan, X. et al. Identification of the gene encoding the enzyme deficient in mucopolysaccharidosis IIIC (Sanfilippo disease type C). Am. J. Hum. Genet. 79, 738–744 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Durand, S., Feldhammer, M., Bonneil, E., Thibault, P. & Pshezhetsky, A. V. Analysis of the biogenesis of heparan sulfate acetyl-CoA:α-glucosaminide N-acetyltransferase provides insights into the mechanism underlying its complete deficiency in mucopolysaccharidosis IIIC. J. Biol. Chem. 285, 31233–31242 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Efeyan, A., Zoncu, R. & Sabatini, D. M. Amino acids and mTORC1: from lysosomes to disease. Trends Mol. Med. 18, 524–533 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Inoki, K., Li, Y., Xu, T. & Guan, K. L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17, 1829–1834 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. 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  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank T. Braulke, A. De Matteis, J. Irazoqui, D. Rubinsztein, D. Sabatini, P. Saftig and R. Zoncu for the helpful suggestions, G. Diez-Roux for helpful discussions and support during manuscript preparation and E. Abrams for manuscript editing. They acknowledge the support of the Italian Telethon Foundation (TGM11CB6, to C.S. and A.B), the Beyond Batten Disease Foundation (to C.S. and A.B.), the European Research Council Advanced Investigator (250154, to A.B.), March of Dimes (#6-FY11-306, to A.B) and the US National Institutes of Health (R01-NS078072, to A.B).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andrea Ballabio.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

The Telethon Institute of Genetics and Medicine

Glossary

Glycocalyx

The polysaccharide-based coating on the inner side of a lysosomal membrane that protects this organelle from digestion by lysosomal enzymes.

Autophagosomes

Intracytoplasmic vacuoles that contain elements of the cytoplasm of a cell. They fuse with lysosomes, and the contents are subjected to enzymatic digestion.

Danon disease

An X-linked dominant disorder caused by mutations in the gene encoding lysosome-associated membrane protein 2 (LAMP2). It predominantly affects cardiac muscle.

Niemann–Pick disease type C1

An autosomal recessive lipid storage disorder that is caused by mutation in the NPC1 (Niemann Pick type C1) gene. It is characterized by progressive neurodegeneration.

Lysosome-related organelles

(LROs). Cell type-specific compartments that include melanosomes, lytic granules, major histocompatibility complex class II compartments, platelet-dense granules, basophil granules, azurophil granules and Drosophila melanogaster pigment granules.

Wolman's disease

An early-onset fulminant disorder of infancy with substantial infiltration of several organs, including the spleen and the liver, by macrophages filled with cholesteryl esters and triglycerides. It is caused by mutations in the gene encoding lipase A.

Multiple sulphatase deficiency

(MSD). An autosomal recessive inherited disease that is caused by mutations in the sulphatase-modifying factor 1 (SUMF1) gene.

Mucopolysaccharidosis

(MPS). A metabolic disorder that is caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules.

Gaucher's disease

An autosomal recessive lysosomal storage disorder due to the deficient activity of β-glucocerebrosidase.

Fronto-temporal dementia

A disorder associated with fronto-temporal lobar degeneration.

Charcot–Marie–Tooth type 2B

Autosomal dominant peripheral sensory neuropathy due to mutations in the late endosomal small GTPase RAB7.

Neuronal ceroid lipofuscinosis

A clinically and genetically heterogeneous group of neurodegenerative disorders that are characterized by the intracellular accumulation of autofluorescent lipopigment storage material.

Pompe's disease

An autosomal recessive inherited disease, also known as glycogen storage disease II. This prototypic lysosomal storage disease is caused by mutations in the gene encoding acid α-1,4-glucosidase.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Settembre, C., Fraldi, A., Medina, D. et al. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol 14, 283–296 (2013). https://doi.org/10.1038/nrm3565

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3565

This article is cited by

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