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Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

Key Points

  • Autophagy is a catabolic process through which eukaryotic cells degrade disposable, ectopic or damaged cytoplasmic material.

  • The inhibition or hyperactivation of autophagy has been linked to the pathogenesis of a wide range of clinically relevant conditions that affect all organs, including neurodegeneration, cardiac disorders and cancer.

  • Pharmacological or nutritional interventions that activate or inhibit autophagy are expected to mediate beneficial effects in multiple clinical settings.

  • The development of clinically viable modulators of autophagy has been hampered by specificity issues, technical problems and murine models that suffer from multiple limitations.

  • Overcoming these obstacles is key to obtaining further insights into autophagy and its intricate relationship with other cellular processes, and hence to unlocking the full therapeutic potential of autophagy modulators.


Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Accordingly, alterations in autophagy have been linked to clinically relevant conditions as diverse as cancer, neurodegeneration and cardiac disorders. Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics. However, such efforts have not yet generated clinically viable interventions. In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic.

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Figure 1: Autophagic processes amenable to therapeutic modulation.
Figure 2: Principles of autophagy modulation.


  1. 1

    Noda, N. N. & Inagaki, F. Mechanisms of autophagy. Annu. Rev. Biophys. 44, 101–122 (2015). This comprehensive review describes the molecular mechanisms that control autophagic responses and their regulation.

    CAS  PubMed  Google Scholar 

  2. 2

    Li, W. W., Li, J. & Bao, J. K. Microautophagy: lesser-known self-eating. Cell. Mol. Life Sci. 69, 1125–1136 (2012).

    CAS  PubMed  Google Scholar 

  3. 3

    Cuervo, A. M. & Wong, E. Chaperone-mediated autophagy: roles in disease and aging. Cell Res. 24, 92–104 (2014).

    CAS  PubMed  Google Scholar 

  4. 4

    Green, D. R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109–1112 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Sica, V. et al. Organelle-specific initiation of autophagy. Mol. Cell 59, 522–539 (2015).

    CAS  PubMed  Google Scholar 

  6. 6

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011). This article demonstrates that autophagy is strictly required for mouse cancer cells that succumb to some chemotherapeutics to release danger signals and hence alert the immune system of a threatening situation.

    CAS  PubMed  Google Scholar 

  9. 9

    Galluzzi, L., Bravo- San Pedro, J. M., Blomgren, K. & Kroemer, G. Autophagy in acute brain injury. Nat. Rev. Neurosci. 17, 467–484 (2016).

    CAS  PubMed  Google Scholar 

  10. 10

    Martinez, J. et al. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat. Cell Biol. 17, 893–906 (2015). This is the first identification of molecules that are specifically required for LAP but dispensable for canonical autophagy, including RUBCN.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Kenific, C. M., Wittmann, T. & Debnath, J. Autophagy in adhesion and migration. J. Cell Sci. 129, 3685–3693 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

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

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Rubinsztein, D. C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709–730 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).

    CAS  PubMed  Google Scholar 

  16. 16

    Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003). References 15 and 16 provide the first demonstration that the Becn1−/− genotype is embryonically lethal and that Becn1+/− mice are more susceptible to spontaneous carcinogenesis than their wild-type littermates.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Yoshii, S. R. et al. Systemic analysis of Atg5-null mice rescued from neonatal lethality by transgenic ATG5 expression in neurons. Dev. Cell 39, 116–130 (2016).

    CAS  PubMed  Google Scholar 

  18. 18

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

    CAS  Google Scholar 

  19. 19

    Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006). References 18 and 19 were the first to demonstrate that neuron-specific deletion of Atg5 or Atg7 causes a progressive neurodegenerative disorder that is associated with premature mortality.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Ross, C. A. & Poirier, M. A. Opinion: what is the role of protein aggregation in neurodegeneration? Nat. Rev. Mol. Cell Biol. 6, 891–898 (2005).

    CAS  PubMed  Google Scholar 

  21. 21

    Menzies, F. M., Fleming, A. & Rubinsztein, D. C. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci. 16, 345–357 (2015).

    CAS  PubMed  Google Scholar 

  22. 22

    Crews, L. et al. Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of α-synucleinopathy. PLoS ONE 5, e9313 (2010).

    PubMed  PubMed Central  Google Scholar 

  23. 23

    Bang, Y., Kim, K. S., Seol, W. & Choi, H. J. LRRK2 interferes with aggresome formation for autophagic clearance. Mol. Cell. Neurosci. 75, 71–80 (2016).

    CAS  PubMed  Google Scholar 

  24. 24

    Vives-Bauza, C. et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl Acad. Sci. USA 107, 378–383 (2010).

    CAS  Google Scholar 

  25. 25

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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440–1446 (2011).

    PubMed  Google Scholar 

  27. 27

    Cirulli, E. T. et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347, 1436–1441 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).

    CAS  PubMed  Google Scholar 

  29. 29

    Aguado, C. et al. Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum. Mol. Genet. 19, 2867–2876 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    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).

    CAS  PubMed  Google Scholar 

  31. 31

    Spilman, P. et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. PLoS ONE 5, e9979 (2010).

    PubMed  PubMed Central  Google Scholar 

  32. 32

    Caccamo, A., Majumder, S., Richardson, A., Strong, R. & Oddo, S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau: effects on cognitive impairments. J. Biol. Chem. 285, 13107–13120 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Vingtdeux, V. et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-β peptide metabolism. J. Biol. Chem. 285, 9100–9113 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

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

    PubMed  Google Scholar 

  35. 35

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

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Spencer, B. et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in α-synuclein models of Parkinson's and Lewy body diseases. J. Neurosci. 29, 13578–13588 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

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

    CAS  PubMed  Google Scholar 

  38. 38

    Siddiqui, A. et al. Mitochondrial quality control via the PGC1α-TFEB signaling pathway is compromised by parkin Q311X mutation but independently restored by rapamycin. J. Neurosci. 35, 12833–12844 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Rodriguez-Navarro, J. A. et al. Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol. Dis. 39, 423–438 (2010).

    CAS  PubMed  Google Scholar 

  40. 40

    Liu, K., Shi, N., Sun, Y., Zhang, T. & Sun, X. Therapeutic effects of rapamycin on MPTP-induced Parkinsonism in mice. Neurochem. Res. 38, 201–207 (2013).

    CAS  PubMed  Google Scholar 

  41. 41

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

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Li, X. Z. et al. Therapeutic effects of valproate combined with lithium carbonate on MPTP-induced parkinsonism in mice: possible mediation through enhanced autophagy. Int. J. Neurosci. 123, 73–79 (2013).

    CAS  PubMed  Google Scholar 

  43. 43

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

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Jiang, J., Jiang, J., Zuo, Y. & Gu, Z. Rapamycin protects the mitochondria against oxidative stress and apoptosis in a rat model of Parkinson's disease. Int. J. Mol. Med. 31, 825–832 (2013).

    CAS  PubMed  Google Scholar 

  45. 45

    Pan, T. et al. Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol. Dis. 32, 16–25 (2008).

    CAS  PubMed  Google Scholar 

  46. 46

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

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Ejlerskov, P. et al. Lack of neuronal IFN-β-IFNAR causes lewy body- and Parkinson's disease-like dementia. Cell 163, 324–339 (2015). This article demonstrates that defective type I interferon signalling promotes parkinsonism in mice, as it imposes an autophagic defect that is accompanied by the accumulation of senescent mitochondria.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Xilouri, M. et al. Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration in rats. Autophagy 12, 2230–2247 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Sarkar, S. et al. A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum. Mol. Genet. 17, 170–178 (2008).

    CAS  PubMed  Google Scholar 

  51. 51

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

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Lee, J. H. et al. Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron 85, 303–315 (2015).

    CAS  PubMed  Google Scholar 

  53. 53

    Castillo, K. et al. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 9, 1308–1320 (2013).

    CAS  PubMed  Google Scholar 

  54. 54

    Zhang, K. et al. Food restriction-induced autophagy modulates degradation of mutant SOD1 in an amyotrophic lateral sclerosis mouse model. Brain Res. 1519, 112–119 (2013).

    CAS  PubMed  Google Scholar 

  55. 55

    Feng, H. L. et al. Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 155, 567–572 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Zhang, X. et al. Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy 7, 412–425 (2011).

    CAS  PubMed  Google Scholar 

  57. 57

    Nassif, M. et al. Pathogenic role of BECN1/Beclin 1 in the development of amyotrophic lateral sclerosis. Autophagy 10, 1256–1271 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Guha, P., Harraz, M. M. & Snyder, S. H. Cocaine elicits autophagic cytotoxicity via a nitric oxide-GAPDH signaling cascade. Proc. Natl Acad. Sci. USA 113, 1417–1422 (2016).

    CAS  PubMed  Google Scholar 

  59. 59

    Sutton, L. P. & Caron, M. G. Essential role of D1R in the regulation of mTOR complex1 signaling induced by cocaine. Neuropharmacology 99, 610–619 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Wu, J., McCallum, S. E., Glick, S. D. & Huang, Y. Inhibition of the mammalian target of rapamycin pathway by rapamycin blocks cocaine-induced locomotor sensitization. Neuroscience 172, 104–109 (2011).

    CAS  PubMed  Google Scholar 

  61. 61

    Mehta, A., Prabhakar, M., Kumar, P., Deshmukh, R. & Sharma, P. L. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Eur. J. Pharmacol. 698, 6–18 (2013).

    CAS  PubMed  Google Scholar 

  62. 62

    Stamoula, E. et al. Low dose administration of glutamate triggers a non-apoptotic, autophagic response in PC12 cells. Cell. Physiol. Biochem. 37, 1750–1758 (2015).

    CAS  PubMed  Google Scholar 

  63. 63

    Wang, Y. et al. An autophagic mechanism is involved in apoptotic death of rat striatal neurons induced by the non-N-methyl-D-aspartate receptor agonist kainic acid. Autophagy 4, 214–226 (2008).

    CAS  PubMed  Google Scholar 

  64. 64

    Perez-Carrion, M. D. et al. Dendrimer-mediated siRNA delivery knocks down Beclin 1 and potentiates NMDA-mediated toxicity in rat cortical neurons. J. Neurochem. 120, 259–268 (2012).

    CAS  PubMed  Google Scholar 

  65. 65

    Kulbe, J. R., Mulcahy Levy, J. M., Coultrap, S. J., Thorburn, A. & Bayer, K. U. Excitotoxic glutamate insults block autophagic flux in hippocampal neurons. Brain Res. 1542, 12–19 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Giorgi, F. S., Biagioni, F., Lenzi, P., Frati, A. & Fornai, F. The role of autophagy in epileptogenesis and in epilepsy-induced neuronal alterations. J. Neural Transm. (Vienna) 122, 849–862 (2015).

    Google Scholar 

  67. 67

    McMahon, J. et al. Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis. J. Neurosci. 32, 15704–15714 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Zeng, L. H., Xu, L., Gutmann, D. H. & Wong, M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol. 63, 444–453 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Zhou, J. et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J. Neurosci. 29, 1773–1783 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Zeng, L. H. et al. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum. Mol. Genet. 20, 445–454 (2011).

    CAS  PubMed  Google Scholar 

  71. 71

    Chang, C. F. et al. Melatonin attenuates kainic acid-induced neurotoxicity in mouse hippocampus via inhibition of autophagy and α-synuclein aggregation. J. Pineal Res. 52, 312–321 (2012).

    CAS  PubMed  Google Scholar 

  72. 72

    Ginet, V. et al. Involvement of autophagy in hypoxic-excitotoxic neuronal death. Autophagy 10, 846–860 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Zheng, Y. et al. Inhibition of autophagy contributes to melatonin-mediated neuroprotection against transient focal cerebral ischemia in rats. J. Pharmacol. Sci. 124, 354–364 (2014).

    CAS  PubMed  Google Scholar 

  74. 74

    Papadakis, M. et al. Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy. Nat. Med. 19, 351–357 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Wang, P. et al. Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1-dependent adenosine monophosphate-activated kinase pathway. Ann. Neurol. 69, 360–374 (2011).

    CAS  PubMed  Google Scholar 

  76. 76

    Zhang, X. et al. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy 9, 1321–1333 (2013).

    CAS  PubMed  Google Scholar 

  77. 77

    Buckley, K. M. et al. Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. Exp. Transl Stroke Med. 6, 8 (2014).

    PubMed  PubMed Central  Google Scholar 

  78. 78

    Zhang, X. et al. Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: involvement of PARK2-dependent mitophagy. Autophagy 10, 1801–1813 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Sheng, R. et al. Autophagy activation is associated with neuroprotection in a rat model of focal cerebral ischemic preconditioning. Autophagy 6, 482–494 (2010).

    CAS  PubMed  Google Scholar 

  80. 80

    Su, J., Zhang, T., Wang, K., Zhu, T. & Li, X. Autophagy activation contributes to the neuroprotection of remote ischemic perconditioning against focal cerebral ischemia in rats. Neurochem. Res. 39, 2068–2077 (2014).

    CAS  PubMed  Google Scholar 

  81. 81

    Jiang, T. et al. Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy. Br. J. Pharmacol. 171, 3146–3157 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Jiang, T. et al. Ischemic preconditioning provides neuroprotection by induction of AMP-activated protein kinase-dependent autophagy in a rat model of ischemic stroke. Mol. Neurobiol. 51, 220–229 (2015).

    CAS  PubMed  Google Scholar 

  83. 83

    Zheng, Y. Q., Liu, J. X., Li, X. Z., Xu, L. & Xu, Y. G. RNA interference-mediated downregulation of Beclin1 attenuates cerebral ischemic injury in rats. Acta Pharmacol. Sin. 30, 919–927 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Cui, D. R. et al. Propofol prevents cerebral ischemia-triggered autophagy activation and cell death in the rat hippocampus through the NF-κB/p53 signaling pathway. Neuroscience 246, 117–132 (2013).

    CAS  PubMed  Google Scholar 

  85. 85

    Zheng, C. et al. NAD+ administration decreases ischemic brain damage partially by blocking autophagy in a mouse model of brain ischemia. Neurosci. Lett. 512, 67–71 (2012).

    CAS  PubMed  Google Scholar 

  86. 86

    Wen, Y. D. et al. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy 4, 762–769 (2008).

    CAS  PubMed  Google Scholar 

  87. 87

    Kubota, C. et al. Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J. Biol. Chem. 285, 667–674 (2010).

    CAS  PubMed  Google Scholar 

  88. 88

    Xin, X. Y. et al. 2-Methoxyestradiol attenuates autophagy activation after global ischemia. Can. J. Neurol. Sci. 38, 631–638 (2011).

    PubMed  Google Scholar 

  89. 89

    Liu, N., Shang, J., Tian, F., Nishi, H. & Abe, K. In vivo optical imaging for evaluating the efficacy of edaravone after transient cerebral ischemia in mice. Brain Res. 1397, 66–75 (2011).

    CAS  PubMed  Google Scholar 

  90. 90

    Carloni, S., Buonocore, G. & Balduini, W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol. Dis. 32, 329–339 (2008).

    CAS  PubMed  Google Scholar 

  91. 91

    Koike, M. et al. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am. J. Pathol. 172, 454–469 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Xie, C. et al. Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury. Autophagy 12, 410–423 (2016). This report provides compelling evidence in support of the concept that efficient autophagic responses in the neurons of newborns contribute to the aetiology of neonatal asphyxia.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Puyal, J., Vaslin, A., Mottier, V. & Clarke, P. G. Postischemic treatment of neonatal cerebral ischemia should target autophagy. Ann. Neurol. 66, 378–389 (2009).

    CAS  PubMed  Google Scholar 

  94. 94

    Liu, Y. et al. Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. Proc. Natl Acad. Sci. USA 110, 20364–20371 (2013). This is the first description of the mechanisms and pathophysiological relevance of autosis, which is an instance of autophagic cell death that also relies on the plasma membrane Na+/K+-ATPase and hence can be inhibited by cardiac glycosides.

    CAS  Google Scholar 

  95. 95

    Wang, Z. Y., Liu, W. G., Muharram, A., Wu, Z. Y. & Lin, J. H. Neuroprotective effects of autophagy induced by rapamycin in rat acute spinal cord injury model. Neuroimmunomodulation 21, 257–267 (2014).

    PubMed  Google Scholar 

  96. 96

    Jing, C. H. et al. Autophagy activation is associated with neuroprotection against apoptosis via a mitochondrial pathway in a rat model of subarachnoid hemorrhage. Neuroscience 213, 144–153 (2012).

    CAS  PubMed  Google Scholar 

  97. 97

    Chen, J. et al. Melatonin-enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage. J. Pineal Res. 56, 12–19 (2014).

    CAS  PubMed  Google Scholar 

  98. 98

    Shao, A. et al. Enhancement of autophagy by histone deacetylase inhibitor Trichostatin A ameliorates neuronal apoptosis after subarachnoid hemorrhage in rats. Mol. Neurobiol. 53, 18–27 (2016).

    CAS  PubMed  Google Scholar 

  99. 99

    Zhao, H. et al. Role of autophagy in early brain injury after subarachnoid hemorrhage in rats. Mol. Biol. Rep. 40, 819–827 (2013).

    CAS  PubMed  Google Scholar 

  100. 100

    Zhou, Y. et al. Retinoic acid prevents disruption of blood-spinal cord barrier by Iinducing autophagic flux after spinal cord injury. Neurochem. Res. 41, 813–825 (2015).

    CAS  PubMed  Google Scholar 

  101. 101

    Erlich, S., Alexandrovich, A., Shohami, E. & Pinkas-Kramarski, R. Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol. Dis. 26, 86–93 (2007).

    CAS  PubMed  Google Scholar 

  102. 102

    Song, Q., Xie, D., Pan, S. & Xu, W. Rapamycin protects neurons from brain contusioninduced inflammatory reaction via modulation of microglial activation. Mol. Med. Rep. 12, 7203–7210 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Viscomi, M. T. et al. Stimulation of autophagy by rapamycin protects neurons from remote degeneration after acute focal brain damage. Autophagy 8, 222–235 (2012).

    CAS  PubMed  Google Scholar 

  104. 104

    Cui, C. M. et al. Chloroquine exerts neuroprotection following traumatic brain injury via suppression of inflammation and neuronal autophagic death. Mol. Med. Rep. 12, 2323–2328 (2015).

    CAS  PubMed  Google Scholar 

  105. 105

    Luo, C. L. et al. Autophagy is involved in traumatic brain injury-induced cell death and contributes to functional outcome deficits in mice. Neuroscience 184, 54–63 (2011).

    CAS  PubMed  Google Scholar 

  106. 106

    Martinet, W., Knaapen, M. W., Kockx, M. M. & De Meyer, G. R. Autophagy in cardiovascular disease. Trends Mol. Med. 13, 482–491 (2007).

    CAS  PubMed  Google Scholar 

  107. 107

    Tanaka, Y. et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406, 902–906 (2000).

    CAS  PubMed  Google Scholar 

  108. 108

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

    CAS  PubMed  Google Scholar 

  109. 109

    Nakai, A. et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat. Med. 13, 619–624 (2007).

    CAS  PubMed  Google Scholar 

  110. 110

    Huang, C. et al. Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1. PLoS ONE 6, e20975 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Liao, X. et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 15, 545–553 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Oka, T. et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485, 251–255 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Tannous, P. et al. Autophagy is an adaptive response in desmin-related cardiomyopathy. Proc. Natl Acad. Sci. USA 105, 9745–9750 (2008).

    CAS  PubMed  Google Scholar 

  114. 114

    Bhuiyan, M. S. et al. Enhanced autophagy ameliorates cardiac proteinopathy. J. Clin. Invest. 123, 5284–5297 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Xie, M. et al. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation 129, 1139–1151 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Sala-Mercado, J. A. et al. Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury. Circulation 122, S179–S184 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Sciarretta, S. et al. Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation 125, 1134–1146 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Finckenberg, P. et al. Caloric restriction ameliorates angiotensin II-induced mitochondrial remodeling and cardiac hypertrophy. Hypertension 59, 76–84 (2012).

    CAS  PubMed  Google Scholar 

  119. 119

    Bostrom, P. et al. C/EBPβ controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell 143, 1072–1083 (2010).

    PubMed  PubMed Central  Google Scholar 

  120. 120

    Shirakabe, A. et al. Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation 133, 1249–1263 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016). This paper shows that the CRM spermidine extends lifespan in mice as it mediates autophagy-dependent cardioprotective effects, and that a spermidine-rich diet is associated with a lower incidence of cardiovascular disorders in humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Garg, S., Bourantas, C. & Serruys, P. W. New concepts in the design of drug-eluting coronary stents. Nat. Rev. Cardiol. 10, 248–260 (2013).

    CAS  PubMed  Google Scholar 

  123. 123

    Marx, S. O. & Marks, A. R. Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation 104, 852–855 (2001).

    CAS  PubMed  Google Scholar 

  124. 124

    Zhu, H. et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J. Clin. Invest. 117, 1782–1793 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Matsui, Y. et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ. Res. 100, 914–922 (2007).

    CAS  PubMed  Google Scholar 

  126. 126

    Xu, X. et al. Diminished autophagy limits cardiac injury in mouse models of type 1 diabetes. J. Biol. Chem. 288, 18077–18092 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Schneider, J. L. & Cuervo, A. M. Liver autophagy: much more than just taking out the trash. Nat. Rev. Gastroenterol. Hepatol. 11, 187–200 (2014).

    PubMed  Google Scholar 

  128. 128

    Sequea, D. A., Sharma, N., Arias, E. B. & Cartee, G. D. Calorie restriction enhances insulin-stimulated glucose uptake and Akt phosphorylation in both fast-twitch and slow-twitch skeletal muscle of 24-month-old rats. J. Gerontol. A Biol. Sci. Med. Sci. 67, 1279–1285 (2012).

    PubMed  PubMed Central  Google Scholar 

  129. 129

    Marcinko, K. et al. High intensity interval training improves liver and adipose tissue insulin sensitivity. Mol. Metab. 4, 903–915 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Cool, B. et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403–416 (2006).

    CAS  PubMed  Google Scholar 

  131. 131

    Hatori, M. et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 15, 848–860 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Leontieva, O. V., Paszkiewicz, G., Demidenko, Z. N. & Blagosklonny, M. V. Resveratrol potentiates rapamycin to prevent hyperinsulinemia and obesity in male mice on high fat diet. Cell Death Dis. 4, e472 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Sun, L. et al. Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway. Am. J. Physiol. Endocrinol. Metab. 309, E925–E935 (2015).

    CAS  PubMed  Google Scholar 

  134. 134

    Lin, C. W. et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J. Hepatol. 58, 993–999 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Kim, K. E. et al. Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism. Sci. Rep. 6, 30111 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Song, Y. M. et al. Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway. Autophagy 11, 46–59 (2015).

    PubMed  Google Scholar 

  137. 137

    Hidvegi, T. et al. An autophagy-enhancing drug promotes degradation of mutant α1-antitrypsin Z and reduces hepatic fibrosis. Science 329, 229–232 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Schreiber, K. H. et al. Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging Cell 14, 265–273 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Mottillo, E. P. et al. Lack of adipocyte AMPK exacerbates insulin resistance and hepatic steatosis through brown and beige adipose tissue function. Cell Metab. 24, 118–129 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Ding, W. X. et al. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology 139, 1740–1752 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Ni, H. M., Du, K., You, M. & Ding, W. X. Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity. Am. J. Pathol. 183, 1815–1825 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Lee, H. Y. et al. Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis. Autophagy 12, 1390–1403 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Sakaguchi, M. et al. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem. Biophys. Res. Commun. 340, 296–301 (2006).

    CAS  PubMed  Google Scholar 

  147. 147

    Ding, D. F. et al. Resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK. Am. J. Nephrol. 31, 363–374 (2010).

    CAS  PubMed  Google Scholar 

  148. 148

    Tikoo, K., Tripathi, D. N., Kabra, D. G., Sharma, V. & Gaikwad, A. B. Intermittent fasting prevents the progression of type I diabetic nephropathy in rats and changes the expression of Sir2 and p53. FEBS Lett. 581, 1071–1078 (2007).

    CAS  PubMed  Google Scholar 

  149. 149

    Jung, H. S. et al. Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab. 8, 318–324 (2008).

    CAS  PubMed  Google Scholar 

  150. 150

    Goginashvili, A. et al. Insulin granules. Insulin secretory granules control autophagy in pancreatic beta cells. Science 347, 878–882 (2015). This article provides compelling evidence in support of the concept that insulin granules are degraded by autophagy in pancreatic β -cells as a mechanism that negatively regulates insulin secretion under fasting conditions.

    CAS  PubMed  Google Scholar 

  151. 151

    Altshuler-Keylin, S. et al. Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance. Cell Metab. 24, 402–419 (2016). This article shows that efficient autophagic responses are required for the beige-to-white fat transition, which is generally coupled to HFD-induced obesity and insulin resistance.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Galluzzi, L. et al. Autophagy in malignant transformation and cancer progression. EMBO J. 34, 856–880 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

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

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Rao, S. et al. A dual role for autophagy in a murine model of lung cancer. Nat. Commun. 5, 3056 (2014).

    PubMed  Google Scholar 

  155. 155

    Strohecker, A. M. et al. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov. 3, 1272–1285 (2013).

    CAS  PubMed  Google Scholar 

  156. 156

    Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2013). References 154–156 provide solid genetic data demonstrating that autophagy inhibits malignant transformation but accelerates tumour progression in the setting of KRAS-driven or BRAF-driven pulmonary or pancreatic carcinogenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Wei, Y. et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 154, 1269–1284 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Maiuri, M. C. et al. Autophagy regulation by p53. Curr. Opin. Cell Biol. 22, 181–185 (2010).

    CAS  PubMed  Google Scholar 

  160. 160

    Wang, R. C. et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338, 956–959 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Galluzzi, L., Bravo- San Pedro, J. M., Demaria, S., Formenti, S. C. & Kroemer, G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat. Rev. Clin. Oncol. 14, 247–258 (2016). This recent review summarizes preclinical and clinical data indicating that autophagy activators, rather than inhibitors, may potentiate the therapeutic effects of anticancer agents that promote, or at least are compatible with, tumour-targeting immune responses.

    PubMed  Google Scholar 

  162. 162

    Guo, J. Y., Xia, B. & White, E. Autophagy-mediated tumor promotion. Cell 155, 1216–1219 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Di Biase, S. et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Ladoire, S. et al. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer. Autophagy 11, 1878–1890 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Puleston, D. J. et al. Autophagy is a critical regulator of memory CD8+ T cell formation. eLife 3, e03706 (2014).

    PubMed  PubMed Central  Google Scholar 

  167. 167

    Pua, H. H., Dzhagalov, I., Chuck, M., Mizushima, N. & He, Y. W. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 204, 25–31 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Thurston, T. L., Ryzhakov, G., Bloor, S., von Muhlinen, N. & Randow, F. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat. Immunol. 10, 1215–1221 (2009).

    CAS  PubMed  Google Scholar 

  169. 169

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

    CAS  Google Scholar 

  170. 170

    Travassos, L. H. et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 11, 55–62 (2010).

    CAS  PubMed  Google Scholar 

  171. 171

    Py, B. F., Lipinski, M. M. & Yuan, J. Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection. Autophagy 3, 117–125 (2007).

    CAS  PubMed  Google Scholar 

  172. 172

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

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Shahnazari, S., Namolovan, A., Mogridge, J., Kim, P. K. & Brumell, J. H. Bacterial toxins can inhibit host cell autophagy through cAMP generation. Autophagy 7, 957–965 (2011).

    CAS  PubMed  Google Scholar 

  174. 174

    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).

    CAS  PubMed  Google Scholar 

  175. 175

    Choy, A. et al. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338, 1072–1076 (2012). This paper identifies a protein from L. pneumophila that operates as a virulence factor by inhibiting autophagy in host cells upon LC3 deconjugation.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

    Dong, N. et al. Structurally distinct bacterial TBC-like GAPs link Arf GTPase to Rab1 inactivation to counteract host defenses. Cell 150, 1029–1041 (2012).

    CAS  Google Scholar 

  177. 177

    Yoshikawa, Y. et al. Listeria monocytogenes ActA-mediated escape from autophagic recognition. Nat. Cell Biol. 11, 1233–1240 (2009).

    CAS  PubMed  Google Scholar 

  178. 178

    Kim, J. J. et al. Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. Cell Host Microbe 11, 457–468 (2012).

    CAS  PubMed  Google Scholar 

  179. 179

    Kuo, S. Y. et al. Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics. Proc. Natl Acad. Sci. USA 112, E4281–E4287 (2015).

    CAS  PubMed  Google Scholar 

  180. 180

    Lapaquette, P., Bringer, M. A. & Darfeuille-Michaud, A. Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response. Cell. Microbiol. 14, 791–807 (2012).

    CAS  PubMed  Google Scholar 

  181. 181

    Miao, Y., Li, G., Zhang, X., Xu, H. & Abraham, S. N. A. TRP channel senses lysosome neutralization by pathogens to trigger their expulsion. Cell 161, 1306–1319 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

    Lee, S. et al. Carbon monoxide confers protection in sepsis by enhancing beclin 1-dependent autophagy and phagocytosis. Antioxid. Redox Signal. 20, 432–442 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Gong, L. et al. The Burkholderia pseudomallei type III secretion system and BopA are required for evasion of LC3-associated phagocytosis. PLoS ONE 6, e17852 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Lam, G. Y., Cemma, M., Muise, A. M., Higgins, D. E. & Brumell, J. H. Host and bacterial factors that regulate LC3 recruitment to Listeria monocytogenes during the early stages of macrophage infection. Autophagy 9, 985–995 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185

    Manzanillo, P. S. et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501, 512–516 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186

    Kimmey, J. M. et al. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature 528, 565–569 (2015). This report demonstrates that ATG5, but not several other components of the canonical autophagic machinery, in monocytes is required for mice to normally control M. tuberculosis infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

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

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Gutierrez, M. G. et al. Autophagy induction favours the generation and maturation of the Coxiella-replicative vacuoles. Cell. Microbiol. 7, 981–993 (2005).

    CAS  PubMed  Google Scholar 

  189. 189

    Niu, H., Xiong, Q., Yamamoto, A., Hayashi-Nishino, M. & Rikihisa, Y. Autophagosomes induced by a bacterial Beclin 1 binding protein facilitate obligatory intracellular infection. Proc. Natl Acad. Sci. USA 109, 20800–20807 (2012). This study provides robust evidence in support of the notion that A. phagocytophilum actively promotes BECN1-dependent autophagic responses in host cells to acquire nutrients for growth.

    CAS  PubMed  Google Scholar 

  190. 190

    Raoult, D. et al. Treatment of Q fever endocarditis: comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine. Arch. Intern. Med. 159, 167–173 (1999).

    CAS  PubMed  Google Scholar 

  191. 191

    Orvedahl, A. et al. Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480, 113–117 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Liang, X. H. et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J. Virol. 72, 8586–8596 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193

    Sumpter, R. Jr. et al. Fanconi anemia proteins function in mitophagy and immunity. Cell 165, 867–881 (2016). This is the first demonstration that members of the FANC protein family participate not only in the DNA damage response but also in virophagy and mitophagy.

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194

    Orvedahl, A. et al. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1, 23–35 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

    Shelly, S., Lukinova, N., Bambina, S., Berman, A. & Cherry, S. Autophagy is an essential component of Drosophila immunity against vesicular stomatitis virus. Immunity 30, 588–598 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196

    Roy, J., Paquette, J. S., Fortin, J. F. & Tremblay, M. J. The immunosuppressant rapamycin represses human immunodeficiency virus type 1 replication. Antimicrob. Agents Chemother. 46, 3447–3455 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    Shoji-Kawata, S. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198

    Nicoletti, F. et al. Inhibition of human immunodeficiency virus (HIV-1) infection in human peripheral blood leucocytes-SCID reconstituted mice by rapamycin. Clin. Exp. Immunol. 155, 28–34 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199

    Alirezaei, M., Flynn, C. T., Wood, M. R. & Whitton, J. L. Pancreatic acinar cell-specific autophagy disruption reduces coxsackievirus replication and pathogenesis in vivo. Cell Host Microbe 11, 298–305 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

    Nicola, A. M. et al. Macrophage autophagy in immunity to Cryptococcus neoformans and Candida albicans. Infect. Immun. 80, 3065–3076 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201

    Kanayama, M. et al. Autophagy enhances NFκB activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity. Nat. Commun. 6, 5779 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202

    Akoumianaki, T. et al. Aspergillus cell wall melanin blocks LC3-associated phagocytosis to promote pathogenicity. Cell Host Microbe 19, 79–90 (2016).

    CAS  PubMed  Google Scholar 

  203. 203

    Zhao, Z. et al. Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell Host Microbe 4, 458–469 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    Choi, J. et al. The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy. Immunity 40, 924–935 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205

    Selleck, E. M. et al. A noncanonical autophagy pathway restricts Toxoplasma gondii growth in a strain-specific manner in IFN-γ-activated human cells. mBio 6, e01157–15 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206

    Flannery, E. L., Chatterjee, A. K. & Winzeler, E. A. Antimalarial drug discovery — approaches and progress towards new medicines. Nat. Rev. Microbiol. 11, 849–862 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207

    Sullivan, D. J. Jr, Gluzman, I. Y., Russell, D. G. & Goldberg, D. E. On the molecular mechanism of chloroquine's antimalarial action. Proc. Natl Acad. Sci. USA 93, 11865–11870 (1996).

    CAS  PubMed  Google Scholar 

  208. 208

    Roetzer, A., Gratz, N., Kovarik, P. & Schuller, C. Autophagy supports Candida glabrata survival during phagocytosis. Cell. Microbiol. 12, 199–216 (2010).

    CAS  PubMed  Google Scholar 

  209. 209

    Deretic, V., Saitoh, T. & Akira, S. Autophagy in infection, inflammation and immunity. Nat. Rev. Immunol. 13, 722–737 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210

    Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).

    CAS  PubMed  Google Scholar 

  211. 211

    Shi, C. S. et al. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13, 255–263 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212

    Dang, J. et al. Gene–gene interaction of ATG5, ATG7, BLK and BANK1 in systemic lupus erythematosus. Int. J. Rheum. Dis. 19, 1284–1293 (2016).

    CAS  PubMed  Google Scholar 

  213. 213

    Martinez, J. et al. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature 533, 115–119 (2016). This report elegantly proves that LAP defects, but not defects in canonical autophagy, are associated with impaired efferocytosis, secretion of pro-inflammatory cytokines and spontaneous onset of an SLE-like disorder in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  214. 214

    Remijsen, Q. et al. Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res. 21, 290–304 (2011).

    CAS  PubMed  Google Scholar 

  215. 215

    Lee, S. J., Silverman, E. & Bargman, J. M. The role of antimalarial agents in the treatment of SLE and lupus nephritis. Nat. Rev. Nephrol. 7, 718–729 (2011).

    CAS  PubMed  Google Scholar 

  216. 216

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 217

    Henckaerts, L. et al. Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease. Inflamm. Bowel Dis. 17, 1392–1397 (2011).

    PubMed  Google Scholar 

  218. 218

    Kaul, A. et al. Systemic lupus erythematosus. Nat. Rev. Dis. Primers 2, 16039 (2016).

    PubMed  Google Scholar 

  219. 219

    Matsuda, C. et al. Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis. Clin. Exp. Immunol. 148, 348–359 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. 220

    Dumortier, J. et al. Everolimus for refractory Crohn's disease: a case report. Inflamm. Bowel Dis. 14, 874–877 (2008).

    PubMed  Google Scholar 

  221. 221

    Yang, Z., Fujii, H., Mohan, S. V., Goronzy, J. J. & Weyand, C. M. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J. Exp. Med. 210, 2119–2134 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223

    Yoshizaki, A. et al. Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Arthritis Rheum. 62, 2476–2487 (2010).

    CAS  PubMed  Google Scholar 

  224. 224

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. 225

    Prevel, N., Allenbach, Y., Klatzmann, D., Salomon, B. & Benveniste, O. Beneficial role of rapamycin in experimental autoimmune myositis. PLoS ONE 8, e74450 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. 226

    Esposito, M. et al. Rapamycin inhibits relapsing experimental autoimmune encephalomyelitis by both effector and regulatory T cells modulation. J. Neuroimmunol. 220, 52–63 (2010).

    CAS  PubMed  Google Scholar 

  227. 227

    Zhang, Z. et al. Low dose rapamycin exacerbates autoimmune experimental uveitis. PLoS ONE 7, e36589 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. 228

    Teachey, D. T. et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br. J. Haematol. 145, 101–106 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. 229

    Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).

    CAS  Google Scholar 

  230. 230

    Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).

    CAS  PubMed  Google Scholar 

  231. 231

    Morselli, E. et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis. 1, e10 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. 232

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

    CAS  Google Scholar 

  233. 233

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

    PubMed  Google Scholar 

  234. 234

    Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). This is the first demonstration that administering rapamycin late in life extends the lifespan of mice independently of their genetic background.

    CAS  PubMed  PubMed Central  Google Scholar 

  235. 235

    Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. 236

    Pyo, J. O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4, 2300 (2013).

    PubMed  PubMed Central  Google Scholar 

  237. 237

    Colman, R. J. et al. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat. Commun. 5, 3557 (2014).

    PubMed  PubMed Central  Google Scholar 

  238. 238

    Madeo, F., Zimmermann, A., Maiuri, M. C. & Kroemer, G. Essential role for autophagy in life span extension. J. Clin. Invest. 125, 85–93 (2015).

    PubMed  PubMed Central  Google Scholar 

  239. 239

    Lopez-Otin, C., Galluzzi, L., Freije, J. M., Madeo, F. & Kroemer, G. Metabolic control of longevity. Cell 166, 802–821 (2016). This recent review dissects the intimate relationship between metabolism and ageing, highlighting several points of intervention at which strategies that support metabolic fitness may extend healthy lifespan in humans.

    CAS  PubMed  Google Scholar 

  240. 240

    Yang, L. et al. Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle. Cell Rep. 14, 422–428 (2016).

    CAS  PubMed  Google Scholar 

  241. 241

    Patel, A. S. et al. Autophagy in idiopathic pulmonary fibrosis. PLoS ONE 7, e41394 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. 242

    Lee, S. J. et al. Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension. Am. J. Respir. Crit. Care Med. 183, 649–658 (2011).

    CAS  PubMed  Google Scholar 

  243. 243

    Luciani, A. et al. Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat. Cell Biol. 12, 863–875 (2010).

    CAS  PubMed  Google Scholar 

  244. 244

    Chung, E. J. et al. Mammalian target of rapamycin inhibition with rapamycin mitigates radiation-induced pulmonary fibrosis in a murine model. Int. J. Radiat. Oncol. Biol. Phys. 96, 857–866 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  245. 245

    Wang, W. et al. mTORC1 is involved in hypoxia-induced pulmonary hypertension through the activation of Notch3. J. Cell. Physiol. 229, 2117–2125 (2014).

    CAS  PubMed  Google Scholar 

  246. 246

    Sureshbabu, A. et al. Inhibition of regulatory-associated protein of mechanistic target of rapamycin prevents hyperoxia-induced lung injury by enhancing autophagy and reducing apoptosis in neonatal mice. Am. J. Respir. Cell Mol. Biol. 55, 722–735 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. 247

    Hu, Y. et al. Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury. Autophagy 12, 2286–2299 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. 248

    Chen, Z. H. et al. Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. Proc. Natl Acad. Sci. USA 107, 18880–18885 (2010).

    CAS  PubMed  Google Scholar 

  249. 249

    Lam, H. C. et al. Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction. J. Clin. Invest. 123, 5212–5230 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. 250

    Mizumura, K. et al. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Invest. 124, 3987–4003 (2014). This paper shows that mitophagic responses participate in the pathogenesis of COPD.

    CAS  PubMed  PubMed Central  Google Scholar 

  251. 251

    Chen, Z. H. et al. Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS ONE 3, e3316 (2008).

    PubMed  PubMed Central  Google Scholar 

  252. 252

    Hartleben, B. et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Invest. 120, 1084–1096 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. 253

    Kawakami, T. et al. Deficient autophagy results in mitochondrial dysfunction and FSGS. J. Am. Soc. Nephrol. 26, 1040–1052 (2015).

    CAS  PubMed  Google Scholar 

  254. 254

    Oliva Trejo, J. A. et al. Transient increase in proteinuria, poly-ubiquitylated proteins and ER stress markers in podocyte-specific autophagy-deficient mice following unilateral nephrectomy. Biochem. Biophys. Res. Commun. 446, 1190–1196 (2014).

    CAS  PubMed  Google Scholar 

  255. 255

    Zeng, C. et al. Podocyte autophagic activity plays a protective role in renal injury and delays the progression of podocytopathies. J. Pathol. 234, 203–213 (2014).

    CAS  PubMed  Google Scholar 

  256. 256

    Cinque, L. et al. FGF signalling regulates bone growth through autophagy. Nature 528, 272–275 (2015).

    CAS  PubMed  Google Scholar 

  257. 257

    Chen, J. & Long, F. mTORC1 signaling controls mammalian skeletal growth through stimulation of protein synthesis. Development 141, 2848–2854 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. 258

    Yang, G. E. et al. Rapamycin-induced autophagy activity promotes bone fracture healing in rats. Exp. Ther. Med. 10, 1327–1333 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. 259

    Alvarez-Garcia, O. et al. Rapamycin induces growth retardation by disrupting angiogenesis in the growth plate. Kidney Int. 78, 561–568 (2010).

    CAS  PubMed  Google Scholar 

  260. 260

    Holstein, J. H. et al. Rapamycin affects early fracture healing in mice. Br. J. Pharmacol. 154, 1055–1062 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. 261

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

    CAS  PubMed  PubMed Central  Google Scholar 

  262. 262

    Raben, N. et al. Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder — murine Pompe disease. Autophagy 6, 1078–1089 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  263. 263

    Raben, N. et al. Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease. Hum. Mol. Genet. 17, 3897–3908 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. 264

    Awad, O. et al. Altered TFEB-mediated lysosomal biogenesis in Gaucher disease iPSC-derived neuronal cells. Hum. Mol. Genet. 24, 5775–5788 (2015).

    CAS  PubMed  Google Scholar 

  265. 265

    Maetzel, D. et al. Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann–Pick Type C patient-specific iPS cells. Stem Cell Rep. 2, 866–880 (2014).

    CAS  Google Scholar 

  266. 266

    Zhou, Z. et al. Autophagy supports color vision. Autophagy 11, 1821–1832 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  267. 267

    Rodriguez-Muela, N. et al. Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa. Cell Death Differ. 22, 476–487 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  268. 268

    Kim, J. Y. et al. Noncanonical autophagy promotes the visual cycle. Cell 154, 365–376 (2013). This article was the first to demonstrate that LAP is essential for the degradation of photoreceptor outer segments phagocytosed by the retinal epithelium in the course of the visual cycle.

    CAS  PubMed  PubMed Central  Google Scholar 

  269. 269

    Santeford, A. et al. Impaired autophagy in macrophages promotes inflammatory eye disease. Autophagy 12, 1876–1885 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. 270

    Selmi, C. Diagnosis and classification of autoimmune uveitis. Autoimmun. Rev. 13, 591–594 (2014).

    CAS  PubMed  Google Scholar 

  271. 271

    Rezaie, T. et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295, 1077–1079 (2002).

    CAS  PubMed  Google Scholar 

  272. 272

    Fingert, J. H. et al. Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Hum. Mol. Genet. 20, 2482–2494 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  273. 273

    Chi, Z. L. et al. Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice. Hum. Mol. Genet. 19, 2606–2615 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  274. 274

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

    PubMed  PubMed Central  Google Scholar 

  275. 275

    Lee, I. H. et al. Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress. Science 336, 225–228 (2012). This study characterizes one of the autophagy-independent functions of ATG7, namely, the regulation of p53 activity in the course of metabolic stress.

    CAS  PubMed  PubMed Central  Google Scholar 

  276. 276

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

    CAS  PubMed  PubMed Central  Google Scholar 

  277. 277

    Rodriguez-Boulan, E., Kreitzer, G. & Musch, A. Organization of vesicular trafficking in epithelia. Nat. Rev. Mol. Cell Biol. 6, 233–247 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. 278

    Calne, R. Y. et al. Rapamycin for immunosuppression in organ allografting. Lancet 2, 227 (1989).

    CAS  PubMed  Google Scholar 

  279. 279

    Taherian, E., Rao, A., Malemud, C. J. & Askari, A. D. The biological and clinical activity of anti-malarial drugs in autoimmune disorders. Curr. Rheumatol. Rev. 9, 45–62 (2013).

    CAS  PubMed  Google Scholar 

  280. 280

    Maes, H. et al. Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 26, 190–206 (2014). This report elegantly demonstrates that chloroquine exerts robust anticancer effects through its ability to promote tumour vessel normalization independent of autophagy.

    CAS  PubMed  Google Scholar 

  281. 281

    Eng, C. H. et al. Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy. Proc. Natl Acad. Sci. USA 113, 182–187 (2016).

    CAS  PubMed  Google Scholar 

  282. 282

    Niso-Santano, M. et al. Unsaturated fatty acids induce non-canonical autophagy. EMBO J. 34, 1025–1041 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  283. 283

    Kaizuka, T. et al. An autophagic flux probe that releases an internal control. Mol. Cell 64, 835–849 (2016).

    CAS  PubMed  Google Scholar 

  284. 284

    Cabrera, S. et al. ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis. Autophagy 9, 1188–1200 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  285. 285

    Barinaga, M. Knockout mice: round two. Science 265, 26–28 (1994).

    CAS  PubMed  Google Scholar 

  286. 286

    Blaney Davidson, E. N., van de Loo, F. A., van den Berg, W. B. & van der Kraan, P. M. How to build an inducible cartilage-specific transgenic mouse. Arthritis Res. Ther. 16, 210 (2014).

    PubMed  Google Scholar 

  287. 287

    Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  288. 288

    Kroemer, G. et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 16, 3–11 (2009).

    CAS  PubMed  Google Scholar 

  289. 289

    Galluzzi, L. et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 22, 58–73 (2015).

    CAS  PubMed  Google Scholar 

  290. 290

    Berry, D. L. & Baehrecke, E. H. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 131, 1137–1148 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  291. 291

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

    CAS  PubMed  Google Scholar 

  292. 292

    Galluzzi, L., Pietrocola, F., Levine, B. & Kroemer, G. Metabolic control of autophagy. Cell 159, 1263–1276 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  293. 293

    Nishida, Y. et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461, 654–658 (2009). This was the first characterization of a non-canonical, ATG5-independent and ATG7-independent autophagic response in mouse cells.

    CAS  Google Scholar 

  294. 294

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

    CAS  PubMed  Google Scholar 

  295. 295

    Ronan, B. et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat. Chem. Biol. 10, 1013–1019 (2014).

    CAS  Google Scholar 

  296. 296

    Bago, R. et al. Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase. Biochem. J. 463, 413–427 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  297. 297

    Akin, D. et al. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 10, 2021–2035 (2014).

    PubMed  PubMed Central  Google Scholar 

  298. 298

    Egan, D. F. et al. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol. Cell 59, 285–297 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  299. 299

    Petherick, K. J. et al. Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy. J. Biol. Chem. 290, 11376–11383 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  300. 300

    Yap, T. A., Sandhu, S. K., Workman, P. & de Bono, J. S. Envisioning the future of early anticancer drug development. Nat. Rev. Cancer 10, 514–523 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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Owing to space limitations, the authors apologize to the authors of several high-quality articles in the field for not being able to discuss and cite their work. L.G. is supported by the Department of Radiation Oncology of Weill Cornell Medical College (intramural funds) and Sotio a.c. J.M.B.-S.P. and G.K. are supported by the French Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR), Projets blancs; ANR under the frame of the programme E-Rare-2, the European Research Area (ERA)-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Institut Universitaire de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LeDucq Foundation; the LabEx Immuno-Oncology; the Site de Recherche Intégrée sur le Cancer (SIRIC) Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). B.L. is supported by the National Institutes of Health, Cancer Prevention Research Institute of Texas, and the LeDucq Foundation. D.R.G. is supported by the National Institutes of Health and the American Lebanese Syrian Associated Charities (ALSAC).

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PowerPoint slides


Autophagic cell death

A variant of regulated cell death (RCD) that is precipitated by the autophagic machinery and hence can be retarded with pharmacological or genetic inhibitors of autophagy.

Regulated cell death

(RCD). A form of cell death that relies on the activation of genetically encoded machinery and hence can be retarded or accelerated with specific pharmacological or genetic interventions.


Autophagic response that is specific for depolarized or otherwise damaged mitochondria.


Autophagic response that is specific for intracellular protein aggregates, which often are highly ubiquitylated.

Presenilin 1

(PSEN1). Component of the γ-secretase complex that contributes to the accumulation of amyloid plaques in the brain of patients with Alzheimer disease (AD).

Autophagic adaptor

A protein that directs autophagic substrates to forming autophagosomes through its capacity to bind ubiquitylated structures and lipidated Atg8 family members.

Amyloid-β precursor protein

(APP). A protein that — upon cleavage — accounts for the majority of amyloid plaques in the brain of patients with Alzheimer disease (AD).

Caloric restriction mimetic

(CRM). A molecule that mimics the biochemical and cellular effects of fasting, including autophagy activation and cytosolic acetyl-CoA depletion, but does not provoke a sizeable weight loss.


A natural α-linked disaccharide that potently activates autophagy through poorly characterized mechanisms.


A widely used antiepileptic drug that induces autophagy by affecting myo-inositol-1,4,5-trisphosphate levels.


An antidepressant that promotes autophagic responses by altering myo-inositol-1,4,5-trisphosphate levels.

Locomotor sensitization

Long-lasting exacerbation of a psychostimulant-induced locomotor response, which is brought about by repeated intermittent administration of the same psychoactive agent.

Ischaemic preconditioning

An experimental technique for increasing the resistance of neurons or cardiomyocytes to prolonged, severe ischaemia based on the repeated administration of short, mild ischaemic episodes.

Cardiac glycoside

A natural compound that exerts positive inotropic effects and retards some forms of autophagic cell death as it inhibits the plasma membrane Na+/K+-ATPase.


The removal of dying or dead cells by professional phagocytes.


A natural polyamine that potently activates autophagy by operating as a caloric restriction mimetic (CRM).

Coronary angioplasty

A minimally invasive surgical procedure for the treatment of narrowed or weakened arteries, which consists of the insertion of a small mesh tube (stent) through the femoral artery.


An antidiabetic agent with pleiotropic effects, including the capacity to trigger autophagy by acting as a caloric restriction mimetic (CRM).

db/db mice

Mice homozygous for the spontaneous db (for diabetes) mutation in leptin receptor (Lepr), which causes limited leptin signalling. These animals are commonly used as models for type 2 diabetes and metabolic syndrome.

ob/ob mice

Mice homozygous for the spontaneous ob (for obesity) mutation in leptin receptor (Lepr), which causes absent leptin signalling. These animals are commonly used as models for obesity and metabolic syndrome.


A widely used antiepileptic drug that induces autophagy by altering myo-inositol-1,4,5-triphosphate levels.

α1-antitrypsin deficiency

A genetic disease that causes the defective production of serpin family A member 1 (SERPINA1; also known as α1-antitrypsin) in the lungs and liver, which results in pulmonary disorders that are often associated with hepatic symptoms.


A naturally occurring toxin that is commonly used to generate rodent models of type 1 diabetes owing to its pronounced selectivity for pancreatic β-cells.

Malignant transformation

The conversion of a healthy, normal cell into a neoplastic cell precursor. Malignant transformation is insufficient to drive tumorigenesis.

Oncosuppressor genes

Genes mutated or silenced in familial or sporadic forms of cancer. Many of these genes encode proteins that are involved in the maintenance of cellular homeostasis or in the activation of regulated cell death (RCD).


Genes overexpressed or hyperactivated in familial or sporadic forms of cancer. Many of these genes encode positive regulators of cellular proliferation or proteins that inhibit regulated cell death (RCD).

Tumour progression

A process through which a neoplastic cell precursor acquires additional genetic or epigenetic alterations that allow it to escape cell-intrinsic and cell-extrinsic control mechanisms and form aggressive tumours.


A process in which the immune system recognizes and eliminates a potentially dangerous entity, including invading pathogens as well as pre-malignant and malignant cells.


Supramolecular platforms that support caspase 1 activation, hence allowing for the proteolytic maturation and secretion of pro-inflammatory interleukin-1β (IL-1β) and IL-18.

Neutrophil extracellular traps

(NETs). Chromatin-based and granule protein-containing fibres that are released by neutrophils to immobilize and kill invading microorganisms.

Cellular senescence

A permanent proliferative arrest that is generally associated with specific morphological and biochemical features, including the secretion of multiple cytokines and other biologically active factors.

Chronic obstructive pulmonary disease

(COPD). A progressive lung disease that is characterized by long-term limited airflow, which is often caused or aggravated by tobacco smoke.

Focal segmental glomerulosclerosis

A leading cause of kidney failure in adults that is characterized by the degeneration of sections of the glomerulus with a focal (as opposed to diffuse) intrarenal distribution.


A sphingolipid that accumulates in patients with Gaucher disease (mostly in the macrophages) as a result of mutations in glucosylceramidase beta (GBA).

Retinitis pigmentosa

An inherited, degenerative eye disease that causes severe vision impairment owing to the progressive degeneration of the rod photoreceptor cells.


Rapamycin derivatives with improved pharmacodynamic and pharmacokinetic properties.

Canonical autophagy

A term commonly used to refer to an autophagic response that is dependent on autophagy-related 5 (ATG5), ATG7, beclin 1 (BECN1) and phosphatidylinositol-3-phosphate (PtdIns3P) production.

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Galluzzi, L., Bravo-San Pedro, J., Levine, B. et al. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov 16, 487–511 (2017).

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