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The role of lysosomes in metabolic and autoimmune diseases

Nature Reviews Nephrology volume 19, pages 366–383 (2023)Cite this article

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Abstract

Lysosomes are catabolic organelles that contribute to the degradation of intracellular constituents through autophagy and of extracellular components through endocytosis, phagocytosis and macropinocytosis. They also have roles in secretory mechanisms, the generation of extracellular vesicles and certain cell death pathways. These functions make lysosomes central organelles in cell homeostasis, metabolic regulation and responses to environment changes including nutrient stresses, endoplasmic reticulum stress and defects in proteostasis. Lysosomes also have important roles in inflammation, antigen presentation and the maintenance of long-lived immune cells. Their functions are tightly regulated by transcriptional modulation via TFEB and TFE3, as well as by major signalling pathways that lead to activation of mTORC1 and mTORC2, lysosome motility and fusion with other compartments. Lysosome dysfunction and alterations in autophagy processes have been identified in a wide variety of diseases, including autoimmune, metabolic and kidney diseases. Deregulation of autophagy can contribute to inflammation, and lysosomal defects in immune cells and/or kidney cells have been reported in inflammatory and autoimmune pathologies with kidney involvement. Defects in lysosomal activity have also been identified in several pathologies with disturbances in proteostasis, including autoimmune and metabolic diseases such as Parkinson disease, diabetes mellitus and lysosomal storage diseases. Targeting lysosomes is therefore a potential therapeutic strategy to regulate inflammation and metabolism in a variety of pathologies.

Key points

  • Lysosomes are versatile organelles that can associate with several other cell compartments, resulting in a variety of functions including roles in autophagy, endocytosis, phagocytosis, secretory mechanisms and cell death pathways.

  • Lysosomes are dynamic, motile organelles that respond to intracellular and extracellular stimuli and are subject to numerous changes according to their environment; the composition, number and size of lysosomes are finely regulated.

  • Lysosomes have vital functions in cell homeostasis and metabolic regulation as well as in the immune system, including roles in phagocytosis, antigen processing and inflammation; disruption of these functions can lead to metabolic, autoimmune and kidney diseases.

  • Small molecules and peptides that can specifically target lysosomes might be valuable therapeutics, capable of correcting dysfunctions of crucial lysosome-dependent pathways and their immune and metabolic consequences.

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Fig. 1: Overview of the endolysosomal autophagy system.
Fig. 2: Functions of lysosomal proteins.
Fig. 3: Lysosomal activity in health and disease.

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References

  1. Rousseau, A. & Bertolotti, A. Regulation of proteasome assembly and activity in health and disease. Nat. Rev. Mol. Cell Biol. 19, 697–712 (2018).

    Article  CAS  PubMed  Google Scholar 

  2. Hetz, C., Zhang, K. & Kaufman, R. J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 21, 421–438 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. Wang, L. et al. The emerging mechanisms and functions of microautophagy. Nat. Rev. Mol. Cell Biol. 24, 186–203 (2023).

    Article  CAS  PubMed  Google Scholar 

  6. Kaushik, S. & Cuervo, A. M. The coming of age of chaperone-mediated autophagy. Nat. Rev. Mol. Cell Biol. 19, 365–381 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cullen, P. J. & Steinberg, F. To degrade or not to degrade: mechanisms and significance of endocytic recycling. Nat. Rev. Mol. Cell Biol. 19, 679–696 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Galluzzi, L. et al. Molecular definitions of autophagy and related processes. EMBO J. 36, 1811–1836 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Heckmann, B. L. & Green, D. R. LC3-associated phagocytosis at a glance. J. Cell Sci. 132, jcs222984 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ligeon, L.-A., Loi, M. & Münz, C. LC3-associated phagocytosis and antigen presentation. Curr. Protoc. Immunol. 123, e60 (2018).

    Article  PubMed  Google Scholar 

  12. Leidal, A. M. & Debnath, J. Emerging roles for the autophagy machinery in extracellular vesicle biogenesis and secretion. FASEB Bioadv. 3, 377–386 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. 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 

  15. 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 

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

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. Pols, M. S. et al. hVps41 and VAMP7 function in direct TGN to late endosome transport of lysosomal membrane proteins. Nat. Commun. 4, 1361 (2013).

    Article  PubMed  Google Scholar 

  19. Coutinho, M. F., Prata, M. J. & Alves, S. A shortcut to the lysosome: the mannose-6-phosphate-independent pathway. Mol. Genet. Metab. 107, 257–266 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. Gan, N. et al. Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P2 and rapamycin. Proc. Natl Acad. Sci. USA 119, e2120404119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Talaia, G., Amick, J. & Ferguson, S. M. Receptor-like role for PQLC2 amino acid transporter in the lysosomal sensing of cationic amino acids. Proc. Natl Acad. Sci. USA 118, e2014941118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee, J. H. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hong, W. & Lev, S. Tethering the assembly of SNARE complexes. Trends Cell Biol. 24, 35–43 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Bröcker, C., Engelbrecht-Vandré, S. & Ungermann, C. Multisubunit tethering complexes and their role in membrane fusion. Curr. Biol. 20, R943–R952 (2010).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Morgan, A. J., Platt, F. M., Lloyd-Evans, E. & Galione, A. Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease. Biochem. J. 439, 349–378 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Skowyra, M. L., Schlesinger, P. H., Naismith, T. V. & Hanson, P. I. Triggered recruitment of ESCRT machinery promotes endolysosomal repair. Science 360, 6384 (2018).

    Article  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. 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 

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

    Article  PubMed  PubMed Central  Google Scholar 

  39. Settembre, C. 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 

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

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wang, W. 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 

  42. Li, Y. Protein kinase C controls lysosome biogenesis independently of mTORC1. Nat. Cell Biol. 18, 1065–1077 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Annunziata, I. 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 

  44. Yang, L., Zhang, L., Wu, Q. & Boyd, D. D. Unbiased screening for transcriptional targets of ZKSCAN3 identifies integrin β4 and vascular endothelial growth factor as downstream targets. J. Biol. Chem. 283, 35295–35304 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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 

  47. Martínez-Fábregas, J. 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 

  48. Liu, B. STAT3 associates with vacuolar H+-ATPase and regulates cytosolic and lysosomal pH. Cell Res. 28, 996–1012 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hao, F. et al. Rheb localized on the Golgi membrane activates lysosome-localized mTORC1 at the Golgi-lysosome contact site. J. Cell Sci. 131, jcs208017 (2018).

    PubMed  Google Scholar 

  50. Bonifacino, J. S. & Neefjes, J. Moving and positioning the endolysosomal system. Curr. Opin. Cell Biol. 47, 1–8 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Friedman, J. R., Dibenedetto, J. R., West, M., Rowland, A. A. & Voeltz, G. K. Endoplasmic reticulum-endosome contact increases as endosomes traffic and mature. Mol. Biol. Cell 24, 1030–1040 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Starling, G. P. Folliculin directs the formation of a Rab34-RILP complex to control the nutrient-dependent dynamic distribution of lysosomes. EMBO Rep. 17, 823–841 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Angarola, B. & Ferguson, S. M. Coordination of Rheb lysosomal membrane interactions with mTORC1 activation. F1000Res. 9(F1000 Faculty Rev), 450 (2020).

    Article  CAS  Google Scholar 

  55. Angarola, B. & Ferguson, S. M. Weak membrane interactions allow Rheb to activate mTORC1 signaling without major lysosome enrichment. Mol. Biol. Cell 30, 2750–2760 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jia, R. & Bonifacino, J. S. Lysosome positioning influences mTORC2 and AKT signaling. Mol. Cell 75, 26–38.e3 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cioni, J. M. Late endosomes act as mRNA translation platforms and sustain mitochondria in axons. Cell 176, 56–72 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Liao, Y. C. RNA granules hitchhike on lysosomes for long-distance transport, using annexin A11 as a molecular tether. Cell 179, 147–164 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang, F. & Muller, S. Manipulating autophagic processes in autoimmune diseases: a special focus on modulating chaperone-mediated autophagy, an emerging therapeutic target. Front. Immunol. 6, 252 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy 17, 1–382 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Chen, C., Sidransky, E. & Chen, Y. Lyso-IP: uncovering pathogenic mechanisms of lysosomal dysfunction. Biomolecules 12, 616 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Barral, D. C. et al. Current methods to analyze lysosome morphology, positioning, motility and function. Traffic 23, 238–269 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ferreira, A. P. A. & Boucrot, E. Mechanisms of carrier formation during clathrin-independent endocytosis. Trends Cell Biol. 28, 188–200 (2018).

    Article  CAS  PubMed  Google Scholar 

  66. Kaksonen, M. & Roux, A. Mechanisms of clathrin-mediated endocytosis. Nat. Rev. Mol. Cell Biol. 19, 313–326 (2018).

    Article  CAS  PubMed  Google Scholar 

  67. Rennick, J. J., Johnston, A. P. R. & Parton, R. G. Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics. Nat. Nanotechnol. 16, 266–276 (2021).

    Article  CAS  PubMed  Google Scholar 

  68. Reggiori, F. & Klumperman, J. in Lysosomes: Biology, Diseases, and Therapeutics (eds. Maxfield, F. R., Willard, J. M. & Lu, S.) 7–31 (Wiley, 2016).

  69. Pickles, S., Vigié, P. & Youle, R. J. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr. Biol. 28, R170–R185 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chino, H. & Mizushima, N. ER-phagy: quality control and turnover of endoplasmic reticulum. Trends Cell Biol. 30, 384–398 (2020).

    Article  CAS  PubMed  Google Scholar 

  71. Papadopoulos, C. & Meyer, H. Detection and clearance of damaged lysosomes by the endo-lysosomal damage response and lysophagy. Curr. Biol. 27, R1330–R1341 (2017).

    Article  CAS  PubMed  Google Scholar 

  72. Zechner, R., Madeo, F. & Kratky, D. Cytosolic lipolysis and lipophagy: two sides of the same coin. Nat. Rev. Mol. Cell Biol. 18, 671–684 (2017).

    Article  CAS  PubMed  Google Scholar 

  73. Martina, J. A. The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Sci. Signal. 7, ra9 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Buratta, S. et al. Lysosomal exocytosis, exosome release and secretory autophagy: the autophagic- and endo-lysosomal systems go extracellular. Int. J. Mol. Sci. 21, 2576 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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 

  77. Hessvik, N. P. & Llorente, A. Current knowledge on exosome biogenesis and release. Cell. Mol. Life Sci. 75, 193–208 (2018).

    Article  CAS  PubMed  Google Scholar 

  78. Leidal, A. M. et al. The LC3-conjugation machinery specifies the loading of RNA-binding proteins into extracellular vesicles. Nat. Cell Biol. 22, 187–199 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Martinez, J. et al. Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc. Natl Acad. Sci. USA 108, 17396–17401 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Stern, L. J., Potolicchio, I. & Santambrogio, L. MHC class II compartment subtypes: structure and function. Curr. Opin. Immunol. 18, 64–69 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Münz, C. The macroautophagy machinery in MHC restricted antigen presentation. Front. Immunol. 12, 628429 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  82. & Münz, C. Autophagy proteins influence endocytosis for MHC restricted antigen presentation. Semin. Cancer Biol. 66, 110–115 (2020).

    Article  PubMed  Google Scholar 

  83. Peters, P. J. et al. Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J. Exp. Med 173, 1099–1109 (1991).

    Article  CAS  PubMed  Google Scholar 

  84. Yuseff, M. I. et al. Polarized secretion of lysosomes at the B cell synapse couples antigen extraction to processing and presentation. Immunity 35, 361–374 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Arbogast, F. et al. ATG5 is required for B cell polarization and presentation of particulate antigens. Autophagy 15, 280–294 (2019).

    Article  CAS  PubMed  Google Scholar 

  86. Arbogast, F. & Gros, F. Lymphocyte autophagy in homeostasis, activation, and inflammatory diseases. Front. Immunol. 9, 1801 (2018).

    Article  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. Kimmey, J. M. & Stallings, C. L. Bacterial pathogens versus autophagy: implications for therapeutic interventions. Trends Mol. Med. 22, 1060–1076 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gonzalez, C. D., Resnik, R. & Vaccaro, M. I. Secretory autophagy and its relevance in metabolic and degenerative disease. Front. Endocrinol. 11, 266 (2020).

    Article  Google Scholar 

  90. Monteith, A. J. et al. Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus. Proc. Natl Acad. Sci. USA 113, E2142–E2151 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lessard, C. J. et al. Identification of a systemic lupus erythematosus risk locus spanning ATG16L2, FCHSD2, and P2RY2 in Koreans. Arthritis Rheumatol. 68, 1197–1209 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Wang, F., Tasset, I., Cuervo, A. M. & Muller, S. In vivo remodeling of altered autophagy-lysosomal pathway by a phosphopeptide in lupus. Cells 9, E2328 (2020).

    Article  Google Scholar 

  93. Cuervo, A. M. & Dice, J. F. Regulation of lamp2a levels in the lysosomal membrane. Traffic 1, 570–583 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Macri, C. et al. Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide. Autophagy 11, 472–486 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  95. An, N. et al. Chloroquine autophagic inhibition rebalances Th17/Treg-mediated immunity and ameliorates systemic lupus erythematosus. Cell Physiol. Biochem. 44, 412–422 (2017).

    Article  CAS  PubMed  Google Scholar 

  96. Li, B., Wang, F., Schall, N. & Muller, S. Rescue of autophagy and lysosome defects in salivary glands of MRL/lpr mice by a therapeutic phosphopeptide. J. Autoimmun. 90, 132–145 (2018).

    Article  CAS  PubMed  Google Scholar 

  97. Qi, Y.-Y. et al. Increased autophagy is cytoprotective against podocyte injury induced by antibody and interferon-α in lupus nephritis. Ann. Rheum. Dis. 77, 1799–1809 (2018).

    Article  CAS  PubMed  Google Scholar 

  98. Gros, F. et al. Macroautophagy is deregulated in murine and human lupus T lymphocytes. Autophagy 8, 1113–1123 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Alessandri, C. et al. T lymphocytes from patients with systemic lupus erythematosus are resistant to induction of autophagy. FASEB J. 26, 4722–4732 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yuan, Q. et al. WDFY4 is involved in symptoms of systemic lupus erythematosus by modulating B cell fate via noncanonical autophagy. J. Immunol. 1950 201, 2570–2578 (2018).

    CAS  Google Scholar 

  101. Cappel, C., Gonzalez, A. C. & Damme, M. Quantification and characterization of the 5′ exonuclease activity of the lysosomal nuclease PLD3 by a novel cell-based assay. J. Biol. Chem. 296, 100152 (2021).

    Article  CAS  PubMed  Google Scholar 

  102. Zhou, X.-J., Klionsky, D. J. & Zhang, H. Podocytes and autophagy: a potential therapeutic target in lupus nephritis. Autophagy 15, 908–912 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wilhelm, M. et al. Implication of a lysosomal antigen in the pathogenesis of lupus erythematosus. J. Autoimmun. 120, 102633 (2021).

    Article  CAS  PubMed  Google Scholar 

  104. Minota, S., Koyasu, S., Yahara, I. & Winfield, J. Autoantibodies to the heat-shock protein hsp90 in systemic lupus erythematosus. J. Clin. Invest. 81, 106–109 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lassen, K. G. et al. Genetic coding variant in GPR65 alters lysosomal pH and links lysosomal dysfunction with colitis risk. Immunity 44, 1392–1405 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang, S.-L. et al. Intestinal autophagy links psychosocial stress with gut microbiota to promote inflammatory bowel disease. Cell Death Dis. 10, 391 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207–211 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596–604 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Momozawa, Y. et al. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. Nat. Commun. 9, 2427 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730.e22 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Xu, Y., Shen, J. & Ran, Z. Emerging views of mitophagy in immunity and autoimmune diseases. Autophagy 16, 3–17 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Shao, B.-Z. et al. The role of autophagy in inflammatory bowel disease. Front. Physiol. 12, 621132 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Foerster, E. G. et al. How autophagy controls the intestinal epithelial barrier. Autophagy 18, 86–103 (2022).

    Article  CAS  PubMed  Google Scholar 

  114. Tsuboi, K. et al. Autophagy protects against colitis by the maintenance of normal gut microflora and secretion of mucus. J. Biol. Chem. 290, 20511–20526 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Yang, L. et al. Impaired autophagy in intestinal epithelial cells alters gut microbiota and host immune responses. Appl. Environ. Microbiol. 84, e00880-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Mehto, S. et al. The Crohn’s disease risk factor IRGM limits NLRP3 inflammasome activation by impeding its assembly and by mediating its selective autophagy. Mol. Cell 73, 429–445.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Retnakumar, S. V. et al. Targeting the endo-lysosomal autophagy pathway to treat inflammatory bowel diseases. J. Autoimmun. 128, 102814 (2022).

    Article  CAS  PubMed  Google Scholar 

  118. Aiyegbusi, O. et al. Renal disease in primary Sjögren’s syndrome. Rheumatol. Ther. 8, 63–80 (2021).

    Article  PubMed  Google Scholar 

  119. François, H. & Mariette, X. Renal involvement in primary Sjögren syndrome. Nat. Rev. Nephrol. 12, 82–93 (2016).

    Article  PubMed  Google Scholar 

  120. Tanaka, T. et al. LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization. Autophagy 18, 1629–1647 (2022).

    Article  CAS  PubMed  Google Scholar 

  121. Alessandri, C. et al. CD4 T lymphocyte autophagy is upregulated in the salivary glands of primary Sjogren’s syndrome patients and correlates with focus score and disease activity. Arthritis Res. Ther. 19, 178 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Colafrancesco, S. et al. Autophagy occurs in lymphocytes infiltrating Sjögren’s syndrome minor salivary glands and correlates with histological severity of salivary gland lesions. Arthritis Res. Ther. 22, 238 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Voynova, E., Lefebvre, F., Qadri, A. & Muller, S. Correction of autophagy impairment inhibits pathology in the NOD.H-2h4 mouse model of primary Sjögren’s syndrome. J. Autoimmun. 108, 102418 (2020).

    Article  CAS  PubMed  Google Scholar 

  124. Weyand, C. M. & Goronzy, J. J. The immunology of rheumatoid arthritis. Nat. Immunol. 22, 10–18 (2021).

    Article  CAS  PubMed  Google Scholar 

  125. Baier, A., Meineckel, I., Gay, S. & Pap, T. Apoptosis in rheumatoid arthritis. Curr. Opin. Rheumatol. 15, 274–279 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. van Loosdregt, J. et al. Increased autophagy in CD4+ T cells of rheumatoid arthritis patients results in T-cell hyperactivation and apoptosis resistance. Eur. J. Immunol. 46, 2862–2870 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Kumar, P. et al. Molecular mechanisms of autophagic memory in pathogenic T cells in human arthritis. J. Autoimmun. 94, 90–98 (2018).

    Article  CAS  PubMed  Google Scholar 

  128. Vomero, M. et al. Autophagy and rheumatoid arthritis: current knowledges and future perspectives. Front. Immunol. 9, 1577 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Jannat, A., John, P., Bhatti, A. & Hayat, M. Q. Tomorou attenuates progression of rheumatoid arthritis through alteration in ULK-1 independent autophagy pathway in collagen induced arthritis mice model. Cell Death Discov. 5, 142 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Zhu, L. et al. The autophagy level is increased in the synovial tissues of patients with active rheumatoid arthritis and is correlated with disease severity. Mediators Inflamm. 2017, 7623145 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Kato, M., Ospelt, C., Gay, R. E., Gay, S. & Klein, K. Dual role of autophagy in stress-induced cell death in rheumatoid arthritis synovial fibroblasts. Arthritis Rheumatol. 66, 40–48 (2014).

    Article  CAS  PubMed  Google Scholar 

  132. Kim, E. K. et al. IL-17-mediated mitochondrial dysfunction impairs apoptosis in rheumatoid arthritis synovial fibroblasts through activation of autophagy. Cell Death Dis. 8, e2565 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  134. Klionsky, D. J. et al. Autophagy in major human diseases. EMBO J. 40, e108863 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chua, J. P., De Calbiac, H., Kabashi, E. & Barmada, S. J. Autophagy and ALS: mechanistic insights and therapeutic implications. Autophagy 18, 254–282 (2022).

    Article  CAS  PubMed  Google Scholar 

  136. Yuan, P. et al. PLD3 affects axonal spheroids and network defects in Alzheimer’s disease. Nature 612, 328–337 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Keller, C. W. & Lunemann, J. D. Autophagy and autophagy-related proteins in CNS autoimmunity. Front. Immunol. 8, 165 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Muller, S. et al. Autophagy in neuroinflammatory diseases. Autoimmun. Rev. 16, 856–874 (2017).

    Article  CAS  PubMed  Google Scholar 

  139. Misrielal, C., Mauthe, M., Reggiori, F. & Eggen, B. J. L. Autophagy in multiple sclerosis: two sides of the same coin. Front. Cell. Neurosci. 14, 603710 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. van Beek, N., Klionsky, D. J. & Reggiori, F. Genetic aberrations in macroautophagy genes leading to diseases. Biochim. Biophys. Acta Mol. Cell Res. 1865, 803–816 (2018).

    Article  PubMed  Google Scholar 

  141. Igci, M. et al. Gene expression profiles of autophagy-related genes in multiple sclerosis. Gene 588, 38–46 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Bhattacharya, A., Parillon, X., Zeng, S., Han, S. & Eissa, N. T. Deficiency of autophagy in dendritic cells protects against experimental autoimmune encephalomyelitis. J. Biol. Chem. 289, 26525–26532 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Hassanpour, M. et al. Real-state of autophagy signaling pathway in neurodegenerative disease; focus on multiple sclerosis. J. Inflamm. (Lond.) 17, 6 (2020).

    Article  PubMed  Google Scholar 

  144. Brun, S. et al. An autophagy-targeting peptide to treat chronic inflammatory demyelinating polyneuropathies. J. Autoimmun. 92, 114–125 (2018).

    Article  CAS  PubMed  Google Scholar 

  145. Bonam, S. R., Tranchant, C. & Muller, S. Autophagy-lysosomal pathway as potential therapeutic target in Parkinson’s disease. Cells 10, 3547 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Menzies, F. M. et al. Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93, 1015–1034 (2017).

    Article  CAS  PubMed  Google Scholar 

  148. Du, J., Ji, Y., Qiao, L., Liu, Y. & Lin, J. Cellular endo‐lysosomal dysfunction in the pathogenesis of non‐alcoholic fatty liver disease. Liver Int 40, 271–280 (2020).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Czaja, M. J. et al. Functions of autophagy in normal and diseased liver. Autophagy 9, 1131–1158 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Pietrocola, F. & Bravo-San Pedro, J. M. Targeting autophagy to counteract obesity-associated oxidative stress. Antioxid. (Basel) 10, 102 (2021).

    Article  CAS  Google Scholar 

  152. 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 

  153. Guerrero-Ros, I. et al. The negative effect of lipid challenge on autophagy inhibits T cell responses. Autophagy 16, 223–238 (2020).

    Article  CAS  PubMed  Google Scholar 

  154. Madrigal-Matute, J. & Cuervo, A. M. Regulation of liver metabolism by autophagy. Gastroenterology 150, 328–339 (2016).

    Article  CAS  PubMed  Google Scholar 

  155. Hammoutene, A. et al. A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis. J. Hepatol. 72, 528–538 (2020).

    Article  CAS  PubMed  Google Scholar 

  156. Filali-Mouncef, Y. et al. The ménage à trois of autophagy, lipid droplets and liver disease. Autophagy 18, 50–72 (2022).

    Article  CAS  PubMed  Google Scholar 

  157. Kouroumalis, E., Voumvouraki, A., Augoustaki, A. & Samonakis, D. N. Autophagy in liver diseases. World J. Hepatol. 13, 6–65 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Kim, Y., Lee, D.-H., Park, S.-H., Jeon, T.-I. & Jung, C. H. The interplay of microRNAs and transcription factors in autophagy regulation in nonalcoholic fatty liver disease. Exp. Mol. Med. 53, 548–559 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Li, X., Wan, T. & Li, Y. Role of FoxO1 in regulating autophagy in type 2 diabetes mellitus (review). Exp. Ther. Med. 22, 707 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Wan, J. et al. LC3-associated phagocytosis in myeloid cells, a fireman that restrains inflammation and liver fibrosis, via immunoreceptor inhibitory signaling. Autophagy 16, 1526–1528 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Zeigerer, A. et al. Regulation of liver metabolism by the endosomal GTPase Rab5. Cell Rep. 11, 884–892 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Gosis, B. S. et al. Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1. Science 376, eabf8271 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Mizunoe, Y. et al. Association between lysosomal dysfunction and obesity-related pathology: a key knowledge to prevent metabolic syndrome. Int. J. Mol. Sci. 20, 3688 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zoncu, R. & Perera, R. M. Built to last: lysosome remodeling and repair in health and disease. Trends Cell Biol. 32, 597–610 (2022).

    Article  CAS  PubMed  Google Scholar 

  165. Platt, F. M. Emptying the stores: lysosomal diseases and therapeutic strategies. Nat. Rev. Drug. Discov. 17, 133–150 (2018).

    Article  CAS  PubMed  Google Scholar 

  166. Festa, B. P. et al. Impaired autophagy bridges lysosomal storage disease and epithelial dysfunction in the kidney. Nat. Commun. 9, 161 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Jouret, F. et al. Cystic fibrosis is associated with a defect in apical receptor-mediated endocytosis in mouse and human kidney. J. Am. Soc. Nephrol. 18, 707–718 (2007).

    Article  CAS  PubMed  Google Scholar 

  168. Ivanova, M. M., Changsila, E., Iaonou, C. & Goker-Alpan, O. Impaired autophagic and mitochondrial functions are partially restored by ERT in Gaucher and Fabry diseases. PLoS One 14, e0210617 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Meyer-Schwesinger, C. Lysosome function in glomerular health and disease. Cell Tissue Res 385, 371–392 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Lin, Q., Banu, K., Ni, Z., Leventhal, J. S. & Menon, M. C. Podocyte autophagy in homeostasis and disease. J. Clin. Med. 10, 1184 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Kimura, T., Isaka, Y. & Yoshimori, T. Autophagy and kidney inflammation. Autophagy 13, 997–1003 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Wang, L. & Law, H. K. W. The role of autophagy in lupus nephritis. Int. J. Mol. Sci. 16, 25154–25167 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Nakatsuka, A. et al. A vaspin–HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease. Commun. Biol. 4, 373 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Kimura, T. et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J. Am. Soc. Nephrol. 22, 902–913 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Sakashita, M., Tanaka, T. & Inagi, R. Metabolic changes and oxidative stress in diabetic kidney disease. Antioxidants 10, 1143 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Wu, M. et al. Relationship between lysosomal dyshomeostasis and progression of diabetic kidney disease. Cell Death Dis. 12, 958 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Brijmohan, A. S. et al. HDAC6 inhibition promotes transcription factor EB activation and is protective in experimental kidney disease. Front. Pharmacol. 9, 34 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Fukushima, K., Kitamura, S., Tsuji, K., Sang, Y. & Wada, J. Sodium glucose co-transporter 2 inhibitor ameliorates autophagic flux impairment on renal proximal tubular cells in obesity mice. Int. J. Mol. Sci. 21, E4054 (2020).

    Article  Google Scholar 

  179. Gu, X. et al. Kidney disease genetic risk variants alter lysosomal beta-mannosidase (MANBA) expression and disease severity. Sci. Transl. Med. 13, eaaz1458 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Kim, H.-R., Jin, H.-S. & Eom, Y.-B. Association between MANBA gene variants and chronic kidney disease in a Korean population. J. Clin. Med. 10, 2255 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Gros, F. & Muller, S. Pharmacological regulators of autophagy and their link with modulators of lupus disease. Br. J. Pharmacol. 171, 4337–4359 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Palhegyi, A. M., Seranova, E., Dimova, S., Hoque, S. & Sarkar, S. Biomedical implications of autophagy in macromolecule storage disorders. Front. Cell Dev. Biol. 7, 179 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Panda, P. K. et al. Chemical screening approaches enabling drug discovery of autophagy modulators for biomedical applications in human diseases. Front. Cell Dev. Biol. 7, 38 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Retnakumar, S. V. & Muller, S. Pharmacological autophagy regulators as therapeutic agents for inflammatory bowel diseases. Trends Mol. Med. 25, 516–537 (2019).

    Article  CAS  PubMed  Google Scholar 

  185. Cao, M., Luo, X., Wu, K. & He, X. Targeting lysosomes in human disease: from basic research to clinical applications. Signal. Transduct. Target. Ther. 6, 379 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Gonzalez, C. D., Carro Negueruela, M. P., Nicora Santamarina, C., Resnik, R. & Vaccaro, M. I. Autophagy dysregulation in diabetic kidney disease: from pathophysiology to pharmacological interventions. Cells 10, 2497 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Whitmarsh-Everiss, T. & Laraia, L. Small molecule probes for targeting autophagy. Nat. Chem. Biol. 17, 653–664 (2021).

    Article  CAS  PubMed  Google Scholar 

  188. Rockel, J. S. & Kapoor, M. Autophagy: controlling cell fate in rheumatic diseases. Nat. Rev. Rheumatol. 13, 517–531 (2017).

    Article  Google Scholar 

  189. Meng, X. et al. Gypenoside XVII enhances lysosome biogenesis and autophagy flux and accelerates autophagic clearance of amyloid-β through TFEB activation. J. Alzheimers Dis. 52, 1135–1150 (2016).

    Article  CAS  PubMed  Google Scholar 

  190. Renna, M. et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J. Clin. Invest. 121, 3554–3563 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Cuddy, L. K. et al. Farnesyltransferase inhibitor LNK-754 attenuates axonal dystrophy and reduces amyloid pathology in mice. Mol. Neurodegener. 17, 54 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Hollywood, J. A. et al. Use of human induced pluripotent stem cells and kidney organoids to develop a cysteamine/mTOR inhibition combination therapy for cystinosis. J. Am. Soc. Nephrol. 31, 962–982 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Ma, T. et al. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature 603, 159–165 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Tsunemi, T. et al. Increased lysosomal exocytosis induced by lysosomal Ca2+ channel agonists protects human dopaminergic neurons from α-synuclein toxicity. J. Neurosci. 39, 5760–5772 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Chen, C.-C. et al. A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV. Nat. Commun. 5, 4681 (2014).

    Article  CAS  PubMed  Google Scholar 

  196. Bonam, S. R., Muller, S., Bayry, J. & Klionsky, D. J. Autophagy as an emerging target for COVID-19: lessons from an old friend, chloroquine. Autophagy 16, 2260–2266 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Schrezenmeier, E. & Dörner, T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat. Rev. Rheumatol. 16, 155–166 (2020).

    Article  CAS  PubMed  Google Scholar 

  198. Li, M. et al. Gasdermin D maintains bone mass by rewiring the endo-lysosomal pathway of osteoclastic bone resorption. Dev. Cell 57, 2365–2380.e8 (2022).

    Article  CAS  PubMed  Google Scholar 

  199. Voss, M. D. et al. Discovery and pharmacological characterization of a novel small molecule inhibitor of phosphatidylinositol-5-phosphate 4-kinase, type II, beta. Biochem. Biophys. Res. Commun. 449, 327–331 (2014).

    Article  CAS  PubMed  Google Scholar 

  200. Korolenko, T. A., Johnston, T. P. & Vetvicka, V. Lysosomotropic features and autophagy modulators among medical drugs: evaluation of their role in pathologies. Molecules 25, E5052 (2020).

    Article  Google Scholar 

  201. Zhao, Y. G., Codogno, P. & Zhang, H. Machinery, regulation and pathophysiological implications of autophagosome maturation. Nat. Rev. Mol. Cell Biol. 22, 733–750 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Yuan, Z., Wang, S., Tan, X. & Wang, D. New insights into the mechanisms of chaperon-mediated autophagy and implications for kidney diseases. Cells 11, 406 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Page, N. et al. HSC70 blockade by the therapeutic peptide P140 affects autophagic processes and endogenous MHCII presentation in murine lupus. Ann. Rheum. Dis. 70, 837–843 (2011).

    Article  CAS  PubMed  Google Scholar 

  204. Zimmer, R., Scherbarth, H. R., Rillo, O. L., Gomez-Reino, J. J. & Muller, S. Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial. Ann. Rheum. Dis. 72, 1830–1835 (2013).

    Article  CAS  PubMed  Google Scholar 

  205. Schall, N., Talamini, L., Wilhelm, M., Jouvin-Marche, E. & Muller, S. P140 peptide leads to clearance of autoreactive lymphocytes and normalizes immune response in lupus-prone mice. Front. Immunol. 13, 904669 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Wilhelm, M. et al. Lupus regulator peptide P140 represses B-cell differentiation by reducing HLA class II molecule overexpression. Arthritis Rheumatol. 70, 1077–1088 (2018).

    Article  CAS  PubMed  Google Scholar 

  207. Galvão, I. et al. The therapeutic effect of phosphopeptide P140 attenuates inflammation induced by uric acid crystals in gout arthritis mouse model. Cells 11, 3709 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Akiyama, K. et al. Therapeutic effects of peptide P140 in a mouse periodontitis model. Cell. Mol. Life Sci. 79, 518 (2022).

    Article  CAS  PubMed  Google Scholar 

  209. Zhang, Z. et al. Role of lysosomes in physiological activities, diseases, and therapy. J. Hematol. Oncol. 14, 79 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Yim, W. W.-Y., Kurikawa, Y. & Mizushima, N. An exploratory text analysis of the autophagy research field. Autophagy 18, 1648–1661 (2022).

    Article  PubMed  Google Scholar 

  211. Grützkau, A. et al. LAMP-1 and LAMP-2, but not LAMP-3, are reliable markers for activation-induced secretion of human mast cells. Cytometry A 61, 62–68 (2004).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Juste, Y. R. et al. Reciprocal regulation of chaperone-mediated autophagy and the circadian clock. Nat. Cell Biol. 23, 1255–1270 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Seoane, P. I. et al. The NLRP3–inflammasome as a sensor of organelle dysfunction. J. Cell Biol. 219, e202006194 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Wang, H.-T. et al. Insights into ferroptosis, a novel target for the therapy of cancer. Front. Oncol. 12, 812534 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Gómez-Sintes, R., Ledesma, M. D. & Boya, P. Lysosomal cell death mechanisms in aging. Ageing Res. Rev. 32, 150–168 (2016).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  218. Repnik, U., Stoka, V., Turk, V. & Turk, B. Lysosomes and lysosomal cathepsins in cell death. Biochim. Biophys. Acta 1824, 22–33 (2012).

    Article  CAS  PubMed  Google Scholar 

  219. Sargeant, T. J. et al. Stat3 controls cell death during mammary gland involution by regulating uptake of milk fat globules and lysosomal membrane permeabilization. Nat. Cell Biol. 16, 1057–1068 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Loison, F., Xu, Y. & Luo, H. R. Proteinase 3 and serpin B1: a novel pathway in the regulation of caspase-3 activation, neutrophil spontaneous apoptosis, and inflammation. Inflamm. Cell Signal. 1, e462 (2014).

    PubMed  PubMed Central  Google Scholar 

  221. Loison, F. et al. Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation. J. Clin. Invest. 124, 4445–4458 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Bewley, M. A. et al. A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci. PLOS Pathog. 7, e1001262 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank S. Blaise (Reims, France) and J. Wada (Okayama, Japan) for valuable suggestions. S.M. acknowledges the support of the French Centre National de la Recherche Scientifique (CNRS); the University of Strasbourg Institute for Advanced Study (USIAS); the ITI 2021-2028 programme, University of Strasbourg-CNRS-Inserm, IdEx Unistra (ANR-10-IDEX-0002) and SFRI (STRAT’US project, ANR-20-SFRI-0012); The French National Agency for Research (TopGum project ANR-21-CE17-0026); the European Regional Development Fund of the European Union in the context of the INTERREG V Upper Rhine programme; the FHU ARRIMAGE and the OMAGE project granted by Region Grand-Est of France and FEDER. S.M. also thanks the TRANSAUTOPHAGY COST Action (CA15138). F.G. thanks  the French National Agency for Research (AURIGENE and AUTOMATE projects, ANR-20-CE93-001 and ANR-20-CE15-0018), the association des sclérodermiques de France (ASF) and the groupe français de recherche sur la sclérodermie (GFRS); F.G. and S.M. acknowledge the Club francophone de l’autophagie (CFATG).

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Authors and Affiliations

  1. Inserm/Université de Strasbourg, Unit Immuno-Rhumathologie moléculaire, Centre de recherche en biomédecine de Strasbourg, Strasbourg, France

    Frédéric Gros

  2. Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France

    Frédéric Gros & Sylviane Muller

  3. Université de Strasbourg, Faculté des Sciences de la Vie, Strasbourg, France

    Frédéric Gros

  4. CNRS-Université de Strasbourg, Unit Biotechnology and cell signalling, École Supérieure de Biotechnologie de Strasbourg/Strasbourg Drug Discovery and Development Institute (IMS), Strasbourg, France

    Sylviane Muller

  5. University of Strasbourg Institute for Advanced Study, Strasbourg, France

    Sylviane Muller

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Correspondence to Frédéric Gros or Sylviane Muller.

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Glossary

Autophagy

A vital, finely regulated and evolutionarily conserved intracellular pathway that continuously degrades, recycles, and clears unnecessary or dysfunctional cellular components. Autophagy is crucial for cell adaptation to the environment and to maintain cell homeostasis, especially under stress conditions.

Cathepsins

A large family of proteases that are mainly found in acidic endosomal and lysosomal compartments where they have a vital role in intracellular protein degradation, energy metabolism and immune responses.

Efferocytosis

A rapid and efficient process of clearance of apoptotic cells occurring under the control of both professional and non-professional phagocytic cells.

Endocytosis

A vesicle-mediated process by which cells engulf membrane and extracellular material.

Endoplasmic reticulum

A network of tubular membranes that manufacture, process and transport chemical compounds for use inside and outside of the cell.

Endosomal sorting complex required for transport

A multiprotein complex that mediates budding and abscission of intraluminal vesicles into multivesicular endosomes.

Extracellular vesicles

Lipid-bound vesicles that are secreted by cells into the extracellular space. The three main subtypes of extracellular vesicles, microvesicles exosomes and apoptotic bodies, differ according to their biogenesis, release pathways, size, content and function.

Hydroxychloroquine

A lysomotropic compound that increases pH within acidic vacuoles and alters protein degradation by lysosomal acidic hydrolases, assembly of macromolecules in the endosomes and post-translation modification of proteins in the Golgi apparatus.

Lysomotropic agents

Drugs that selectively concentrate inside lysosomes after in vivo administration and exert their cellular effects via lysosomes.

Lysosomal exocytosis

A process in which lysosomes fuse with the plasma membrane and empty their contents outside the cell. This process has an important role in plasma membrane repair, bone resorption, the immune response and elimination of pathogenic substrates.

Mitophagy

A key process that selectively disrupts damaged mitochondria by autolysosomal degradation, preventing excessive generation of reactive oxygen species and activation of cell death.

Phagocytosis

An endocytic process by which phagocytes (for example, macrophages) internalize large particles (>0.5 µm) such as bacteria, other microorganisms, foreign particles and aged red blood cells, to form a phagosome.

Proteasome

A barrel-shaped multiprotein complex composed of proteases that is involved in the selective degradation of intracellular proteins, particularly those marked for proteolysis by ubiquitin. A human cell contains about 30,000 proteasomes.

Trans-Golgi network

A cytosolic apparatus that sorts and transports proteins and some form of lipids to the other cytosolic compartments.

Unfolded protein response

A conserved signalling network that is activated in response to misfolded or unfolded proteins and re-establishes protein homeostasis.

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Gros, F., Muller, S. The role of lysosomes in metabolic and autoimmune diseases. Nat Rev Nephrol 19, 366–383 (2023). https://doi.org/10.1038/s41581-023-00692-2

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