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Balancing lysosome abundance in health and disease

Abstract

Lysosomes are catabolic organelles that govern numerous cellular processes, including macromolecule degradation, nutrient signalling and ion homeostasis. Aberrant changes in lysosome abundance are implicated in human diseases. Here we outline the mechanisms of lysosome biogenesis and turnover, and discuss how changes in the lysosome pool impact physiological and pathophysiological processes.

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Fig. 1: The lysosome and its functions.
Fig. 2: Increasing the lysosome pool.
Fig. 3: Secretion and quality control of lysosomes and lysosomal proteins.
Fig. 4: Cancer cells benefit from enhanced lysosome abundance.

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References

  1. Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lawrence, R. E. & Zoncu, R. The lysosome as a cellular centre for signalling, metabolism and quality control. Nat. Cell Biol. 21, 133–142 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Kim, J., Kundu, M., Viollet, B. & Guan, K.-L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yim, W. W.-Y. & Mizushima, N. Lysosome biology in autophagy. Cell Discov. 6, 6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kim, J. & Guan, K.-L. mTOR as a central hub of nutrient signalling and cell growth. Nat. Cell Biol. 21, 63–71 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. de Araujo, M. E. G., Liebscher, G., Hess, M. W. & Huber, L. A. Lysosomal size matters. Traffic 21, 60–75 (2020).

    Article  PubMed  Google Scholar 

  7. Ballabio, A. & Bonifacino, J. S. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol. 21, 101–118 (2020).

    Article  CAS  PubMed  Google Scholar 

  8. Napolitano, G. & Ballabio, A. TFEB at a glance. J. Cell Sci. 129, 2475–2481 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 

  12. 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 

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

    Article  PubMed  PubMed Central  Google Scholar 

  14. Vega-Rubin-de-Celis, S., Peña-Llopis, S., Konda, M. & Brugarolas, J. Multistep regulation of TFEB by MTORC1. Autophagy 13, 464–472 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Napolitano, G. et al. mTOR-dependent phosphorylation controls TFEB nuclear export. Nat. Commun. 9, 3312 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Martínez-Fábregas, J. et al. Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis. Nat. Commun. 9, 5343 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sakamaki, J.-I. et al. Bromodomain protein BRD4 is a transcriptional repressor of autophagy and lysosomal function. Mol. Cell 66, 517–532 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Annunziata, I. et al. MYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat. Nat. Commun. 10, 3623 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ravichandran, M. et al. Coordinated transcriptional and catabolic programs support iron-dependent adaptation to RAS–MAPK pathway inhibition in pancreatic cancer. Cancer Discov. 12, 2198–2219 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chauhan, S. et al. ZKSCAN3 is a master transcriptional repressor of autophagy. Mol. Cell 50, 16–28 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shingu, T. et al. Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation. Nat. Genet. 49, 75–86 (2017).

    Article  CAS  PubMed  Google Scholar 

  22. Yang, C. & Wang, X. Lysosome biogenesis: regulation and functions. J. Cell Biol. 220, e202102001 (2021).

  23. Coutinho, M. F., Prata, M. J. & Alves, S. Mannose-6-phosphate pathway: a review on its role in lysosomal function and dysfunction. Mol. Genet. Metab. 105, 542–550 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Saftig, P. & Klumperman, J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat. Rev. Mol. Cell Biol. 10, 623–635 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Johnson, D. E., Ostrowski, P., Jaumouillé, V. & Grinstein, S. The position of lysosomes within the cell determines their luminal pH. J. Cell Biol. 212, 677–692 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mutvei, A. P. et al. Rap1-GTPases control mTORC1 activity by coordinating lysosome organization with amino acid availability. Nat. Commun. 11, 1416 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rabanal-Ruiz, Y. et al. mTORC1 activity is supported by spatial association with focal adhesions. J. Cell Biol. 220, e202004010 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pu, J., Guardia, C. M., Keren-Kaplan, T. & Bonifacino, J. S. Mechanisms and functions of lysosome positioning. J. Cell Sci. 129, 4329–4339 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Yin, Q. et al. CDK4/6 regulate lysosome biogenesis through TFEB/TFE3. J. Cell Biol. 219, e201911036 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hung, Y.-H., Chen, L. M.-W., Yang, J.-Y. & Yang, W. Y. Spatiotemporally controlled induction of autophagy-mediated lysosome turnover. Nat. Commun. 4, 2111 (2013).

    Article  PubMed  Google Scholar 

  32. Wang, L., Klionsky, D. J. & Shen, H.-M. The emerging mechanisms and functions of microautophagy. Nat. Rev. Mol. Cell Biol. 24, 186–203 (2022).

    Article  PubMed  Google Scholar 

  33. Thurston, T. L. M., Wandel, M. P., von Muhlinen, N., Foeglein, A. & Randow, F. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482, 414–418 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Maejima, I. et al. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 32, 2336–2347 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Aits, S. & Jäättelä, M. Lysosomal cell death at a glance. J. Cell Sci. 126, 1905–1912 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Bussi, C. et al. Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism. Nat. Commun. 13, 7338 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yoshida, Y. et al. Ubiquitination of exposed glycoproteins by SCFFBXO27 directs damaged lysosomes for autophagy. Proc. Natl Acad. Sci. USA 114, 8574–8579 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chauhan, S. et al. TRIMs and galectins globally cooperate and TRIM16 and Galectin-3 co-direct autophagy in endomembrane damage homeostasis. Dev. Cell 39, 13–27 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Papadopoulos, C., Kravic, B. & Meyer, H. Repair or lysophagy: dealing with damaged lysosomes. J. Mol. Biol. 432, 231–239 (2020).

    Article  CAS  PubMed  Google Scholar 

  40. 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 

  41. Luzio, J. P., Hackmann, Y., Dieckmann, N. M. G. & Griffiths, G. M. The biogenesis of lysosomes and lysosome-related organelles. Cold Spring Harb. Perspect. Biol. 6, a016840 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Bright, N. A., Gratian, M. J. & Luzio, J. P. Endocytic delivery to lysosomes mediated by concurrent fusion and kissing events in living cells. Curr. Biol. 15, 360–365 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McNally, E. K., Karim, M. A. & Brett, C. L. Selective lysosomal transporter degradation by organelle membrane fusion. Dev. Cell 40, 151–167 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Golden, C. K. et al. A two-tiered system for selective receptor and transporter protein degradation. PLoS Genet. 18, e1010446 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yang, X. et al. ESCRT, not intralumenal fragments, sorts ubiquitinated vacuole membrane proteins for degradation. J. Cell Biol. 220, e202012104 (2021).

  47. Zhang, W. et al. A conserved ubiquitin- and ESCRT-dependent pathway internalizes human lysosomal membrane proteins for degradation. PLoS Biol. 19, e3001361 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Oku, M. et al. Evidence for ESCRT- and clathrin-dependent microautophagy. J. Cell Biol. 216, 3263–3274 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhu, L., Jorgensen, J. R., Li, M., Chuang, Y.-S. & Emr, S. D. ESCRTs function directly on the lysosome membrane to downregulate ubiquitinated lysosomal membrane proteins. eLife 6, e26403 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  50. He, C.-W. et al. Membrane recruitment of Atg8 by Hfl1 facilitates turnover of vacuolar membrane proteins in yeast cells approaching stationary phase. BMC Biol. 19, 117 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lee, C., Lamech, L., Johns, E. & Overholtzer, M. Selective lysosome membrane turnover is induced by nutrient starvation. Dev. Cell 55, 289–297 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Andrews, N. W. & Corrotte, M. Plasma membrane repair. Curr. Biol. 28, R392–R397 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Glunde, K. et al. Extracellular acidification alters lysosomal trafficking in human breast cancer cells. Neoplasia 5, 533–545 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Davidson, S. M. & Vander Heiden, M. G. Critical functions of the lysosome in cancer biology. Annu. Rev. Pharmacol. Toxicol. 57, 481–507 (2017).

    Article  CAS  PubMed  Google Scholar 

  55. Xu, J. et al. Chloroquine treatment induces secretion of autophagy-related proteins and inclusion of Atg8-family proteins in distinct extracellular vesicle populations. Autophagy 18, 2547–2560 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Minakaki, G. et al. Autophagy inhibition promotes SNCA/α-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype. Autophagy 14, 98–119 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Solvik, T. A. et al. Secretory autophagy maintains proteostasis upon lysosome inhibition. J. Cell Biol. 221, e202110151 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Radulovic, M. et al. ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. EMBO J. 37, e99753 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Skowyra, M. L., Schlesinger, P. H., Naismith, T. V. & Hanson, P. I. Triggered recruitment of ESCRT machinery promotes endolysosomal repair. Science 360, eaar5078 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Eriksson, I., Wäster, P. & Öllinger, K. Restoration of lysosomal function after damage is accompanied by recycling of lysosomal membrane proteins. Cell Death Dis. 11, 370 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tan, J. X. & Finkel, T. A phosphoinositide signalling pathway mediates rapid lysosomal repair. Nature 609, 815–821 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Radulovic, M. et al. Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair. EMBO J. 41, e112677 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bhattacharya, A. et al. A lysosome membrane regeneration pathway depends on TBC1D15 and autophagic lysosomal reformation proteins. Nat. Cell Biol. 25, 685–698 (2023).

    Article  CAS  PubMed  Google Scholar 

  64. Nakamura, S. et al. LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury. Nat. Cell Biol. 22, 1252–1263 (2020).

    Article  CAS  PubMed  Google Scholar 

  65. Jia, J. et al. Galectins control mTOR in response to endomembrane damage. Mol. Cell 70, 120–135 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cui, Z. et al. Structure of the lysosomal mTORC1–TFEB–Rag–Ragulator megacomplex. Nature 614, 572–579 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Napolitano, G., Di Malta, C. & Ballabio, A. Non-canonical mTORC1 signaling at the lysosome. Trends Cell Biol. 32, 920–931 (2022).

    Article  CAS  PubMed  Google Scholar 

  68. Napolitano, G. et al. A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome. Nature 585, 597–602 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Goodwin, J. M. et al. GABARAP sequesters the FLCN–FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis. Sci. Adv. 7, eabj2485 (2021).

    Article  CAS  PubMed  Google Scholar 

  70. Lawrence, R. E. et al. Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science 366, 971–977 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 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).

    Article  CAS  PubMed  Google Scholar 

  72. SA, N. et al. Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1. Science 380, eabj5559 (2023).

    Article  Google Scholar 

  73. Wang, S. et al. Impaired TFEB-mediated lysosomal biogenesis promotes the development of pancreatitis in mice and is associated with human pancreatitis. Autophagy 15, 1954–1969 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. McGrath, M. J. et al. Defective lysosome reformation during autophagy causes skeletal muscle disease. J. Clin. Invest. 131, e135124 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yorimitsu, T., Nair, U., Yang, Z. & Klionsky, D. J. Endoplasmic reticulum stress triggers autophagy. J. Biol. Chem. 281, 30299–30304 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Korolchuk, V. I. et al. Lysosomal positioning coordinates cellular nutrient responses. Nat. Cell Biol. 13, 453–460 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mejlvang, J. et al. Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy. J. Cell Biol. 217, 3640–3655 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  82. Wang, W. et al. Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation. Proc. Natl Acad. Sci. USA 112, E1373–E1381 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Bandyopadhyay, U. et al. Leucine retention in lysosomes is regulated by starvation. Proc. Natl Acad. Sci. USA 119, e2114912119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Buel, G. R., Dang, H., Asara, J. M., Blenis, J. & Mutvei, A. P. Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1. J. Biol. Chem. 298, 102030 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Germic, N., Frangez, Z., Yousefi, S. & Simon, H.-U. Regulation of the innate immune system by autophagy: neutrophils, eosinophils, mast cells, NK cells. Cell Death Differ. 26, 703–714 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Clarke, A. J. & Simon, A. K. Autophagy in the renewal, differentiation and homeostasis of immune cells. Nat. Rev. Immunol. 19, 170–183 (2019).

    Article  CAS  PubMed  Google Scholar 

  88. Levine, B., Mizushima, N. & Virgin, H. W. Autophagy in immunity and inflammation. Nature 469, 323–335 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Koo, I. C. et al. Role for lysosomal enzyme beta-hexosaminidase in the control of mycobacteria infection. Proc. Natl Acad. Sci. USA 105, 710–715 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Watts, C. Lysosomes and lysosome-related organelles in immune responses. FEBS Open Bio. 12, 678–693 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gray, M. A. et al. Phagocytosis enhances lysosomal and bactericidal properties by activating the transcription factor TFEB. Curr. Biol. 26, 1955–1964 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bretou, M. et al. Lysosome signaling controls the migration of dendritic cells. Sci. Immunol. 2, eaak9573 (2017).

    Article  PubMed  Google Scholar 

  93. Samie, M. & Cresswell, P. The transcription factor TFEB acts as a molecular switch that regulates exogenous antigen-presentation pathways. Nat. Immunol. 16, 729–736 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Pastore, N. et al. TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages. Autophagy 12, 1240–1258 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Tattoli, I. et al. Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program. Cell Host Microbe 11, 563–575 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Visvikis, O. et al. Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes. Immunity 40, 896–909 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mohamud, Y. et al. Coxsackievirus B3 targets TFEB to disrupt lysosomal function. Autophagy 17, 3924–3938 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Campbell, G. R., Rawat, P., Bruckman, R. S. & Spector, S. A. Human immunodeficiency virus type 1 Nef inhibits autophagy through transcription factor EB sequestration. PLoS Pathog. 11, e1005018 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Villegas, F. et al. Lysosomal signaling licenses embryonic stem cell differentiation via inactivation of Tfe3. Cell Stem Cell 24, 257–270 (2019).

    Article  CAS  PubMed  Google Scholar 

  100. Young, N. P. et al. AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes. Genes Dev. 30, 535–552 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Marks, H. et al. The transcriptional and epigenomic foundations of ground state pluripotency. Cell 149, 590–604 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Xu, Y. & Yang, X. Autophagy and pluripotency: self-eating your way to eternal youth. Trends Cell Biol. 32, 868–882 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Gong, J. et al. Phosphorylation of ULK1 by AMPK is essential for mouse embryonic stem cell self-renewal and pluripotency. Cell Death Dis. 9, 38 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Tan, A., Prasad, R. & Jho, E.-H. TFEB regulates pluripotency transcriptional network in mouse embryonic stem cells independent of autophagy-lysosomal biogenesis. Cell Death Dis. 12, 343 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Betschinger, J. et al. Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3. Cell 153, 335–347 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yuizumi, N. et al. Maintenance of neural stem-progenitor cells by the lysosomal biosynthesis regulators TFEB and TFE3 in the embryonic mouse telencephalon. Stem Cells 39, 929–944 (2021).

    Article  CAS  PubMed  Google Scholar 

  107. Kobayashi, T. et al. Enhanced lysosomal degradation maintains the quiescent state of neural stem cells. Nat. Commun. 10, 5446 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  108. García-Prat, L. et al. TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate. Cell Stem Cell 28, 1838–1850 (2021).

    Article  PubMed  Google Scholar 

  109. Mortensen, M. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 208, 455–467 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. García-Prat, L. et al. Autophagy maintains stemness by preventing senescence. Nature 529, 37–42 (2016).

    Article  PubMed  Google Scholar 

  112. Bohl, B., Jabali, A., Ladewig, J. & Koch, P. Asymmetric Notch activity by differential inheritance of lysosomes in human neural stem cells. Sci. Adv. 8, eabl5792 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Loeffler, D. et al. Asymmetric lysosome inheritance predicts activation of haematopoietic stem cells. Nature 573, 426–429 (2019).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Aman, Y. et al. Autophagy in healthy aging and disease. Nat. Aging 1, 634–650 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Liang, R. et al. Restraining lysosomal activity preserves hematopoietic stem cell quiescence and potency. Cell Stem Cell 26, 359–376 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Perera, R. M., Di Malta, C. & Ballabio, A. MiT/TFE family of transcription factors, lysosomes, and cancer. Annu. Rev. Cancer Biol. 3, 203–222 (2019).

    Article  PubMed  Google Scholar 

  118. Kawakami, A. & Fisher, D. E. The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology. Lab. Invest. 97, 649–656 (2017).

    Article  CAS  PubMed  Google Scholar 

  119. Kauffman, E. C. et al. Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers. Nat. Rev. Urol. 11, 465–475 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Argani, P. et al. Primary renal neoplasms with the ASPLTFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am. J. Pathol. 159, 179–192 (2001).

    Article  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Alesi, N. et al. TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism. Nat. Commun. 12, 4245 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Asrani, K. et al. An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN–Rag activation in renal cells with TSC2 loss. Nat. Commun. 13, 6808 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Shin, H. R. & Zoncu, R. The lysosome at the intersection of cellular growth and destruction. Dev. Cell 54, 226–238 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kimmelman, A. C. & White, E. Autophagy and tumor metabolism. Cell Metab. 25, 1037–1043 (2017).

    Article  CAS  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).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Ploper, D. et al. MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells. Proc. Natl Acad. Sci. USA 112, E420–E429 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  129. Zhitomirsky, B. & Assaraf, Y. G. Lysosomal sequestration of hydrophobic weak base chemotherapeutics triggers lysosomal biogenesis and lysosome-dependent cancer multidrug resistance. Oncotarget 6, 1143–1156 (2015).

    Article  PubMed  Google Scholar 

  130. Fassl, A. et al. Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition. Sci. Adv. 6, eabb2210 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhitomirsky, B. & Assaraf, Y. G. Lysosomal accumulation of anticancer drugs triggers lysosomal exocytosis. Oncotarget 8, 45117–45132 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Kundu, S. T. et al. TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins. Nat. Commun. 9, 2731 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Yun, S. et al. TFEB links MYC signaling to epigenetic control of myeloid differentiation and acute myeloid leukemia. Blood Cancer Discov. 2, 162–185 (2021).

    Article  CAS  PubMed  Google Scholar 

  134. Bonam, S. R., Wang, F. & Muller, S. Lysosomes as a therapeutic target. Nat. Rev. Drug Discov. 18, 923–948 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Parenti, G., Medina, D. L. & Ballabio, A. The rapidly evolving view of lysosomal storage diseases. EMBO Mol. Med. 13, e12836 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  137. Lapierre, L. R. et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat. Commun. 4, 2267 (2013).

    Article  PubMed  Google Scholar 

  138. Hughes, A. L. & Gottschling, D. E. An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature 492, 261–265 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Dobrowolski, R. et al. Presenilin deficiency or lysosomal inhibition enhances Wnt signaling through relocalization of GSK3 to the late-endosomal compartment. Cell Rep. 2, 1316–1328 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Yap, C. C., Digilio, L., McMahon, L. P., Garcia, A. D. R. & Winckler, B. Degradation of dendritic cargos requires Rab7-dependent transport to somatic lysosomes. J. Cell Biol. 217, 3141–3159 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Cheng, X.-T. et al. Characterization of LAMP1-labeled nondegradative lysosomal and endocytic compartments in neurons. J. Cell Biol. 217, 3127–3139 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Overly, C. C. & Hollenbeck, P. J. Dynamic organization of endocytic pathways in axons of cultured sympathetic neurons. J. Neurosci. 16, 6056–6064 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Thottacherry, J. J., Sathe, M., Prabhakara, C. & Mayor, S. Spoiled for choice: diverse endocytic pathways function at the cell surface. Annu. Rev. Cell Dev. Biol. 35, 55–84 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Hu, Y.-B., Dammer, E. B., Ren, R.-J. & Wang, G. The endosomal–lysosomal system: from acidification and cargo sorting to neurodegeneration. Transl. Neurodegener. 4, 18 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Demetriades, C., Plescher, M. & Teleman, A. A. Lysosomal recruitment of TSC2 is a universal response to cellular stress. Nat. Commun. 7, 10662 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Menon, S. et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156, 771–785 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Meng, D. et al. ArfGAP1 inhibits mTORC1 lysosomal localization and activation. EMBO J. 40, e106412 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank F. R. Maxfield and T. E. McGraw for helpful discussions. This work was supported by grants from the Swedish Research Council (grant no. 2020-01126), Swedish Cancer Society (grant nos 21 0437 JIA and 20 1188 Pj), Åke Wibergs Foundation, Lars Hierta’s Memory Foundation and Magnus Bergvall Foundation to A.P.M.; and National Institutes of Health grant no. R01 GM051405 to J.B. We apologize to those whose work was not included in this review due to limitations in scope and space.

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Mutvei, A.P., Nagiec, M.J. & Blenis, J. Balancing lysosome abundance in health and disease. Nat Cell Biol 25, 1254–1264 (2023). https://doi.org/10.1038/s41556-023-01197-7

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