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A brief history of autophagy from cell biology to physiology and disease

Nature Cell Biology volume 20, pages 521–527 (2018)Cite this article

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Abstract

The field of autophagy research has developed rapidly since the first description of the process in the 1960s and the identification of autophagy genes in the 1990s. Autophagy is now increasingly studied at the level of organismal pathophysiology and is being connected to the medical sciences. This Historical Perspective describes a brief history of autophagy and discusses unanswered cell biological questions in the field.

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Fig. 1: Key discoveries in the autophagy field.
Fig. 2: Membrane dynamics of the three types of autophagy.
Fig. 3: Potential mechanisms of selective macroautophagy.

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References

  1. Ktistakis, N. T. In praise of M. Anselmier who first used the term “autophagie” in 1859. Autophagy 13, 2015–2017 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Klionsky, D. J. Autophagy revisited: a conversation with Christian de Duve. Autophagy 4, 740–743 (2008).

    Article  PubMed  Google Scholar 

  3. Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728–741 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Stolz, A., Ernst, A. & Dikic, I. Cargo recognition and trafficking in selective autophagy. Nat. Cell Biol. 16, 495–501 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Gatica, D., Lahiri, V. & Klionsky, D. J. Cargo recognition and degradation by selective autophagy. Nat. Cell Biol. 20, 233–242 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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 

  7. Tekirdag, K. A. & Cuervo, A. M. Chaperone-mediated autophagy and endosomal microautophagy: joint by a chaperone. J. Biol. Chem. http://doi.org/cmzv (2017).

  8. Mortimore, G. E. & Pösö, A. R. Intracellular protein catabolism and its control during nutrient deprivation and supply. Annu. Rev. Nutr. 7, 539–564 (1987).

    Article  CAS  PubMed  Google Scholar 

  9. Meijer, A. J. & Codogno, P. Regulation and role of autophagy in mammalian cells. Int. J. Biochem. Cell Biol. 36, 2445–2462 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Kovács, A. L., Pálfia, Z., Réz, G., Vellai, T. & Kávacs, J. Sequestration revisited: integrating traditional electron microscopy, de novo assembly and new results. Autophagy 3, 655–662 (2007).

    Article  PubMed  Google Scholar 

  11. Biazik, J., Vihinen, H., Anwar, T., Jokitalo, E. & Eskelinen, E. L. The versatile electron microscope: an ultrastructural overview of autophagy. Methods 75, 44–53 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Tsukada, M. & Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333, 169–174 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Thumm, M. et al. Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett. 349, 275–280 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Harding, T. M., Morano, K. A., Scott, S. V. & Klionsky, D. J. Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J. Cell Biol. 131, 591–602 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Yuan, W., Tuttle, D. L., Shi, Y. J., Ralph, G. S. & Dunn, W. A. Jr. Glucose-induced microautophagy in Pichia pastoris requires the α-subunit of phosphofructokinase. J. Cell Sci. 110, 1935–1945 (1997).

    CAS  PubMed  Google Scholar 

  16. Sakai, Y., Koller, A., Rangell, L. K., Keller, G. A. & Subramani, S. Peroxisome degradation by microautophagy in Pichia pastoris: identification of specific steps and morphological intermediates. J. Cell Biol. 141, 625–636 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mukaiyama, H. et al. Paz2 and 13 other PAZ gene products regulate vacuolar engulfment of peroxisomes during micropexophagy. Genes. Cell 7, 75–90 (2002).

    CAS  Google Scholar 

  18. Titorenko, V. I., Keizer, I., Harder, W. & Veenhuis, M. Isolation and characterization of mutants impaired in the selective degradation of peroxisomes in the yeast Hansenula polymorpha. J. Bacteriol. 177, 357–363 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Klionsky, D. J. et al. A unified nomenclature for yeast autophagy-related genes. Dev. Cell 5, 539–545 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Parzych, K. R., Ariosa, A., Mari, M. & Klionsky, D. J. A newly characterized vacuolar serine carboxypeptidase, Atg42/Ybr139w, is required for normal vacuole function and the terminal steps of autophagy in the yeast Saccharomyces cerevisiae. Mol. Biol. Cell http://doi.org/cmpc(2018).

  21. Nakatogawa, H., Suzuki, K., Kamada, Y. & Ohsumi, Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat. Rev. Mol. Cell Biol. 10, 458–467 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Tian, Y. et al. C. elegans screen identifies autophagy genes specific to multicellular organisms. Cell 141, 1042–1055 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Muller, O. et al. Autophagic tubes: vacuolar invaginations involved in lateral membrane sorting and inverse vesicle budding. J. Cell Biol. 151, 519–528 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mukaiyama, H. et al. Modification of a ubiquitin-like protein Paz2 conducted micropexophagy through formation of a novel membrane structure. Mol. Biol. Cell 15, 58–70 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Krick, R. et al. Piecemeal microautophagy of the nucleus requires the core macroautophagy genes. Mol. Biol. Cell 19, 4492–4505 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, C. W., Miao, Y. H. & Chang, Y. S. A sterol-enriched vacuolar microdomain mediates stationary phase lipophagy in budding yeast. J. Cell Biol. 206, 357–366 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. van Zutphen, T. et al. Lipid droplet autophagy in the yeast Saccharomyces cerevisiae. Mol. Biol. Cell 25, 290–301 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Tsuji, T. et al. Niemann-Pick type C proteins promote microautophagy by expanding raft-like membrane domains in the yeast vacuole. eLife 6, e25960 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu, X. M. et al. ESCRTs cooperate with a selective autophagy receptor to mediate vacuolar targeting of soluble cargos. Mol. Cell 59, 1035–1042 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. Mukherjee, A., Patel, B., Koga, H., Cuervo, A. M. & Jenny, A. Selective endosomal microautophagy is starvation-inducible in Drosophila. Autophagy 12, 1984–1999 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dice, J. F. Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biol. Sci. 15, 305–309 (1990).

    Article  CAS  Google Scholar 

  35. 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 

  36. Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Tsukamoto, S. et al. Autophagy is essential for preimplantation development of mouse embryos. Science 321, 117–120 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Lim, J. & Yue, Z. Neuronal aggregates: Formation, clearance, and spreading. Dev. Cell 32, 491–501 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Anding, A. L. & Baehrecke, E. H. Cleaning house: selective autophagy of organelles. Dev. Cell 41, 10–22 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Randow, F. & Youle, R. J. Self and nonself: How autophagy targets mitochondria and bacteria. Cell Host Microbe 15, 403–411 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nguyen, T. N., Padman, B. S. & Lazarou, M. Deciphering the molecular signals of PINK1/Parkin mitophagy. Trends Cell Biol. 26, 733–744 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. McWilliams, T. G. et al. Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand. Cell Metab. 27, 439–449 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Haack, T. B. et al. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am. J. Hum. Genet. 91, 1144–1149 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Kim, M. et al. Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. eLife 5, e12245 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  50. 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 

  51. Madeo, F., Tavernarakis, N. & Kroemer, G. Can autophagy promote longevity? Nat. Cell Biol. 12, 842–846 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Lopez-Otin, C., Galluzzi, L., Freije, J. M., Madeo, F. & Kroemer, G. Metabolic control of longevity. Cell 166, 802–821 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Takamura, A. et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 25, 795–800 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Amaravadi, R., Kimmelman, A. C. & White, E. Recent insights into the function of autophagy in cancer. Genes Dev. 30, 1913–1930 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zachari, M. & Ganley, I. G. The mammalian ULK1 complex and autophagy initiation. Essays Biochem. 61, 585–596 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Noda, T. Autophagy in the context of the cellular membrane-trafficking system: the enigma of Atg9 vesicles. Biochem. Soc. Trans. 45, 1323–1331 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kishi-Itakura, C., Koyama-Honda, I., Itakura, E. & Mizushima, N. Ultrastructural analysis of autophagosome organization using mammalian autophagy-deficient cells. J. Cell Sci. 127, 4089–4102 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Noda, T., Fujita, N. & Yoshimori, T. The late stages of autophagy: how does the end begin? Cell Death Differ. 16, 984–990 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Tsuboyama, K. et al. The ATG conjugation systems are important for degradation of the inner autophagosomal membrane. Science 354, 1036–1041 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Nguyen, T. N. et al. Atg8 family LC3/GABARAP proteins are crucial for autophagosome-lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation. J. Cell Biol. 215, 857–874 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Dunn, W. A. Jr. Studies on the mechanisms of autophagy: formation of the autophagic vacuole. J. Cell Biol. 110, 1923–1933 (1990).

    Article  PubMed  Google Scholar 

  62. Axe, E. L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685–701 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Uemura, T. et al. A cluster of thin tubular structures mediates transformation of the ER to autophagic isolation membrane. Mol. Cell. Biol. 34, 1695–1706 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Hayashi-Nishino, M. et al. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 11, 1433–1437 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Yla-Anttila, P., Vihinen, H., Jokitalo, E. & Eskelinen, E. L. 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5, 1180–1185 (2009).

    Article  PubMed  Google Scholar 

  66. Graef, M., Friedman, J. R., Graham, C., Babu, M. & Nunnari, J. ER exit sites are physical and functional core autophagosome biogenesis components. Mol. Biol. Cell 24, 2918–2931 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ge, L., Melville, D., Zhang, M. & Schekman, R. The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. eLife 2, e00947 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  69. Nascimbeni, A. C. et al. ER-plasma membrane contact sites contribute to autophagosome biogenesis by regulation of local PI3P synthesis. EMBO J. 36, 2018–2033 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nishimura, T. et al. Autophagosome formation is initiated at phosphatidylinositol synthase-enriched ER subdomains. EMBO J. 36, 1719–1735 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Noda, N. N., Ohsumi, Y. & Inagaki, F. Atg8-family interacting motif crucial for selective autophagy. FEBS Lett. 581, 1379–1385 (2010).

    Article  CAS  Google Scholar 

  72. Rogov, V. V. et al. Structural and functional analysis of the GABARAP interaction motif (GIM). EMBO Rep. 18, 1382–1396 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kamber, R. A., Shoemaker, C. J. & Denic, V. Receptor-bound targets of selective autophagy use a scaffold protein to activate the Atg1 kinase. Mol. Cell 59, 372–381 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309–314 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Smith, M. D. et al. CCPG1is a non-canonical autophagy cargo receptor essential for ER-phagy and pancreatic ER proteostasis. Dev. Cell 44, 217–232 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Itakura, E. & Mizushima, N. p62 targeting to the autophagosome formation site requires self-oligomerization but not LC3 binding. J. Cell Biol. 192, 17–27 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Itakura, E., Kishi-Itakura, C., Koyama-Honda, I. & Mizushima, N. Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy. J. Cell Sci. 125, 1488–1499 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Li, Y., Lipowsky, R. & Dimova, R. Transition from complete to partial wetting within membrane compartments. J. Am. Chem. Soc. 130, 12252–12253 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Shin, Y. & Brangwynne, C. P. Liquid phase condensation in cell physiology and disease. Science 357, eaaf4382 (2017).

    Article  PubMed  CAS  Google Scholar 

  80. Zhang, Y. et al. SEPA-1 mediates the specific recognition and degradation of P granule components by autophagy in C. elegans. Cell 136, 308–321 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Brangwynne, C. P. et al. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 324, 1729–1732 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Watanabe, T. et al. Genetic visualization of protein interactions harnessing liquid phase transitions. Sci. Rep. 7, 46380 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zaffagnini, G. et al. p62 filaments capture and present ubiquitinated cargos for autophagy. EMBO J. 37, e98308 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Sun, D., Wu, R., Zheng, J., Li, P. & Yu, L. Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation. Cell Res. http://doi.org/cmpd (2018).

  85. Nguyen, N., Shteyn, V. & Melia, T. J. Sensing membrane curvature in macroautophagy. J. Mol. Biol. 429, 457–472 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mi, N. et al. CapZ regulates autophagosomal membrane shaping by promoting actin assembly inside the isolation membrane. Nat. Cell Biol. 17, 1112–1123 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. Seifert, U., Berndl, K. & Lipowsky, R. Shape transformations of vesicles: phase diagram for spontaneous-curvature and bilayer-coupling models. Phys. Rev. A. 44, 1182–1202 (1991).

    Article  CAS  PubMed  Google Scholar 

  88. Knorr, R. L., Dimova, R. & Lipowsky, R. Curvature of double-membrane organelles generated by changes in membrane size and composition. PLoS ONE 7, e32753 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Campelo, F. et al. Sphingomyelin metabolism controls the shape and function of the Golgi cisternae. eLife 6, e24603 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Knorr, R. L., Lipowsky, R. & Dimova, R. Autophagosome closure requires membrane scission. Autophagy 11, 2134–2137 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Yu, S. & Melia, T. J. The coordination of membrane fission and fusion at the end of autophagosome maturation. Curr. Opin. Cell Biol. 47, 92–98 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 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 

  93. Kuma, A., Komatsu, M. & Mizushima, N. Autophagy-monitoring and autophagy-deficient mice. Autophagy 13, 1619–1628 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lu, Q. et al. Homeostatic control of innate lung inflammation by Vici syndrome gene Epg5 and additional autophagy genes promotes influenza pathogenesis. Cell Host Microbe 19, 102–113 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Katayama, H., Kogure, T., Mizushima, N., Yoshimori, T. & Miyawaki, A. A sensitive and quantitative technique for detecting autophagic events based on lysosomal delivery. Chem. Biol. 18, 1042–1052 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Yamashita, S. I. et al. Mitochondrial division occurs concurrently with autophagosome formation but independently of Drp1 during mitophagy. J. Cell Biol. 215, 649–665 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Nishida, Y. et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461, 654–658 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Malhotra, V. Unconventional protein secretion: an evolving mechanism. EMBO J. 32, 1660–1664 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ponpuak, M. et al. Secretory autophagy. Curr. Opin. Cell Biol. 35, 106–116 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Green, D. R. & Levine, B. To be or not to be? How selective autophagy and cell death govern cell fate. Cell 157, 65–75 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Cadwell, K. & Debnath, J. Beyond self-eating: the control of nonautophagic functions and signaling pathways by autophagy-related proteins. J. Cell Biol. 217, 813–822 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  102. Bestebroer, J., V’Kovski, P., Mauthe, M. & Reggiori, F. Hidden behind autophagy: the unconventional roles of ATG proteins. Traffic 14, 1029–1041 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mizushima, N., Yoshimori, T. & Levine, B. Methods in mammalian autophagy research. Cell 140, 313–326 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1–222 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Levine, B., Packer, M. & Codogno, P. Development of autophagy inducers in clinical medicine. J. Clin. Invest. 125, 14–24 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Morel, E. et al. Autophagy: a druggable process. Annu. Rev. Pharmacol. Toxicol. 57, 375–398 (2017).

    Article  CAS  PubMed  Google Scholar 

  107. Mortimore, G. E. & Schworer, C. M. Induction of autophagy by amino-acid deprivation in perfused rat liver. Nature 270, 174–176 (1977).

    Article  CAS  PubMed  Google Scholar 

  108. Pfeifer, U. Inhibition by insulin of the formation of autophagic vacuoles in rat liver: a morphometric approach to the kinetics of intracellular degradation by autophagy. J. Cell Biol. 78, 152–167 (1978).

    Article  CAS  PubMed  Google Scholar 

  109. Seglen, P. O. & Gordon, P. B. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc. Natl. Acad. Sci. USA 79, 1889–1892 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Takeshige, K., Baba, M., Tsuboi, S., Noda, T. & Ohsumi, Y. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J. Cell Biol. 119, 301–311 (1992).

    Article  CAS  PubMed  Google Scholar 

  111. Klionsky, D. J., Cueva, R. & Yaver, D. S. Aminopeptidase I of Saccharomyces cerevisiae is localized to the vacuole independent of the secretory pathway. J. Cell Biol. 119, 287–299 (1992).

    Article  CAS  PubMed  Google Scholar 

  112. Blommaart, E. F., Luiken, J. J., Blommaart, P. J., van Woerkom, G. M. & Meijer, A. J. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J. Biol. Chem. 270, 2320–2326 (1995).

    Article  CAS  PubMed  Google Scholar 

  113. Mizushima, N. et al. A protein conjugation system essential for autophagy. Nature 395, 395–398 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Liang, X. H. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Ichimura, Y. et al. A ubiquitin-like system mediates protein lipidation. Nature 408, 488–492 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kihara, A., Noda, T., Ishihara, N. & Ohsumi, Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J. Cell Biol. 152, 519–530 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ravikumar, B., Duden, R. & Rubinsztein, D. C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet .11, 1107–1117 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037–1040 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Bjørkøy, G. et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. 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 

  123. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Cullup, T. et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat. Genet. 45, 83–87 (2013).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I thank Willa Yim for expert editing of this manuscript, Roland Knorr for stimulating discussions on biomolecular condensates and physical models, and all members of my laboratory for helpful suggestions. This work was supported by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research on Innovative Areas (Grant Numbers 25111001 and 25111005) and JST ERATO (Grant Numbers JPMJER1702).

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  1. Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Noboru Mizushima

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Correspondence to Noboru Mizushima.

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Mizushima, N. A brief history of autophagy from cell biology to physiology and disease. Nat Cell Biol 20, 521–527 (2018). https://doi.org/10.1038/s41556-018-0092-5

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