Molecules and Cells

, Volume 36, Issue 1, pp 7–16 | Cite as

Autophagy: A critical regulator of cellular metabolism and homeostasis

  • Stefan W. Ryter
  • Suzanne M. Cloonan
  • Augustine M. K. Choi


Autophagy is a dynamic process by which cytosolic material, including organelles, proteins, and pathogens, are sequestered into membrane vesicles called autophagosomes, and then delivered to the lysosome for degradation. By recycling cellular components, this process provides a mechanism for adaptation to starvation. The regulation of autophagy by nutrient signals involves a complex network of proteins that include mammalian target of rapamycin, the class III phosphatidylinositol-3 kinase/Beclin 1 complex, and two ubiquitin-like conjugation systems. Additionally, autophagy, which can be induced by multiple forms of chemical and physical stress, including endoplasmic reticulum stress, and hypoxia, plays an integral role in the mammalian stress response. Recent studies indicate that, in addition to bulk assimilation of cytosol, autophagy may proceed through selective pathways that target distinct cargoes to autophagosomes. The principle homeostatic functions of autophagy include the selective clearance of aggregated protein to preserve proteostasis, and the selective removal of dysfunctional mitochondria (mitophagy). Additionally, autophagy plays a central role in innate and adaptive immunity, with diverse functions such as regulation of inflammatory responses, antigen presentation, and pathogen clearance. Autophagy can preserve cellular function in a wide variety of tissue injury and disease states, however, maladaptive or pro-pathogenic outcomes have also been described. Among the many diseases where autophagy may play a role include proteopathies which involve aberrant accumulation of proteins (e.g., neurodegenerative disorders), infectious diseases, and metabolic disorders such as diabetes and metabolic syndrome. Targeting the autophagy pathway and its regulatory components may eventually lead to the development of therapeutics.


autophagy innate immunity metabolism mitophagy neurodegeneration proteostasis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bachar-Wikstrom, E., Wikstrom, J.D., Ariav, Y., Tirosh, B., Kaiser, N., Cerasi, E., and Leibowitz, G. (2013). Stimulation of autophagy improves endoplasmic reticulum stress-induced diabetes. Diabetes 62, 1227–1237.PubMedCrossRefGoogle Scholar
  2. Bodas, M., Tran, I., and Vij, N. (2012). Therapeutic strategies to correct proteostasis-imbalance in chronic obstructive lung diseases. Curr. Mol. Med. 12, 807–814.PubMedCrossRefGoogle Scholar
  3. Boya, P., González-Polo, R.A., Casares, N., Perfettini, J.L., Dessen, P., Larochette, N., Métivier, D., Meley, D., Souquere, S., Yoshimori, T., et al. (2005). Inhibition of macroautophagy triggers apoptosis. Mol. Cell. Biol. 25, 1025–1040.PubMedCrossRefGoogle Scholar
  4. Campbell, G.R., and Spector, S.A. (2011). Hormonally active vitamin D3 (1alpha, 25-dihydroxycholecalciferol) triggers autophagy in human macrophages that inhibits HIV-1 infection. J. Biol. Chem. 286, 18890–18902.PubMedCrossRefGoogle Scholar
  5. Chan, E.Y. (2012). Regulation and function of uncoordinated-51 like kinase proteins. Antioxid. Redox Signal. 17, 775–785.PubMedCrossRefGoogle Scholar
  6. Checroun, C., Wehrly, T.D., Fischer, E.R., Hayes, S.F., and Celli, J. (2006). Autophagy-mediated reentry of Francisella tularensis into the endocytic compartment after cytoplasmic replication. Proc. Natl. Acad. Sci. USA 103, 14578–14583.PubMedCrossRefGoogle Scholar
  7. Chen, Z.H., Kim, H.P., Sciurba, F.C., Lee, S.J., Feghali-Bostwick, C., Stolz, D.B., Dhir, R., Landreneau, R.J., Schuchert, M.J., Yousem, S.A, et al. (2008). Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS One 3, e3316.PubMedCrossRefGoogle Scholar
  8. Choi, A.M., Ryter, S.W., and Levine, B. (2013). Autophagy in human health and disease. N. Engl. J. Med. 368, 651–662.PubMedCrossRefGoogle Scholar
  9. Clausen, T.H., Lamark, T., Isakson, P., Finley, K., Larsen, K.B., Brech, A., Øvervatn, A., Stenmark, H., Bjørkøy, G., Simonsen, A., et al. (2010). p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy. Autophagy 6, 330–344.PubMedCrossRefGoogle Scholar
  10. Dagda, R.K., Cherra, S.J., Kulich, S.M., Tandon, A., Park, D., and Chu, C.T. (2009). Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J. Biol. Chem. 284, 13843–13855.PubMedCrossRefGoogle Scholar
  11. Deretic, V., and Levine, B. (2009). Autophagy, immunity, and microbial adaptations. Cell Host Microbe. 5, 527–549.PubMedCrossRefGoogle Scholar
  12. Elliott, P.R., Bilton, D., and Lomas, D.A. (1998). Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema. Am. J. Respir. Cell Mol. Biol. 18, 670–674.PubMedCrossRefGoogle Scholar
  13. Ganley, I.G., Lam, D.H., Wang, J., Ding, X., Chen, S., and Jiang, X. (2009). ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J. Biol. Chem. 284, 12297–12305.PubMedCrossRefGoogle Scholar
  14. Geisler, S., Holmström, K.M., Skujat, D., Fiesel, F.C., Rothfuss, O.C., Kahle, P.J., and Springer, W. (2010). PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119–131.PubMedCrossRefGoogle Scholar
  15. Gonzalez, C.D., Lee, M.S., Marchetti, P., Pietropaolo, M., Towns, R., Vaccaro, M.I., Watada, H., and Wiley, J.W. (2011). The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy 7, 2–11.PubMedCrossRefGoogle Scholar
  16. Granell, S., Baldini, G., Mohammad, S., Nicolin, V., Narducci, P., Storrie, B., and Baldini, G. (2008). Sequestration of mutated alpha1-antitrypsin into inclusion bodies is a cell-protective mechanism to maintain endoplasmic reticulum function. Mol. Biol. Cell 19, 572–586.PubMedCrossRefGoogle Scholar
  17. Gutierrez, M.G., Vazquez, C.L., Munafo, D.B., Zoppino, F.C., Berón, W., Rabinovitch, M., and Colombo, M.I. (2005). Autophagy induction favours the generation and maturation of the Coxiellareplicative vacuoles. Cell. Microbiol. 7, 981–993.PubMedCrossRefGoogle Scholar
  18. Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 44, 885–889.CrossRefGoogle Scholar
  19. He, C., and Levine, B. (2010). The Beclin 1 interactome. Curr. Opin. Cell Biol. 22, 140–149.PubMedCrossRefGoogle Scholar
  20. He, C., Bassik, M.C., Moresi, V., Sun, K., Wei, Y., Zou, Z., An, Z., Loh, J., Fisher, J., Sun, Q., et al. (2012). Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515.PubMedCrossRefGoogle Scholar
  21. Hidvegi, T., Ewing, M., Hale, P., Dippold, C., Beckett, C., Kemp, C., Maurice, N., Mukherjee, A., Goldbach, C., Watkins, S., et al. (2010). An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 329, 229–232.PubMedCrossRefGoogle Scholar
  22. Hosokawa, N., Hara, T., Kaizuka, T., Kishi, C., Takamura, A., Miura, Y., Iemura, S., Natsume, T., Takehana, K., Yamada, N., et al. (2009). Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991.PubMedCrossRefGoogle Scholar
  23. Hsu, L.J., Hsu, L.J., Sagara, Y., Arroyo, A., Rockenstein, E., Sisk, A., Mallory, M., Wong, J., Takenouchi, T., Hashimoto, M., et al. (2000). alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am. J. Pathol. 157, 401–410.PubMedCrossRefGoogle Scholar
  24. Ichimura, Y., and Komatsu, M. (2010). Selective degradation of p62 by autophagy. Semin. Immunopathol. 32, 431–436.PubMedCrossRefGoogle Scholar
  25. Inoki, K., Zhu, T., and Guan, K.L. (2003). TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590.PubMedCrossRefGoogle Scholar
  26. Imarisio, S., Carmichael, J., Korolchuk, V., Chen, C.W., Saiki, S., Rose, C., Krishna, G., Davies, J.E., Ttofi, E., Underwood, B.R., et al. (2008). Huntington’s disease: from pathology and genetics to potential therapies. Biochem. J. 412, 191–209.PubMedCrossRefGoogle Scholar
  27. Itakura, E., Kishi, C., Inoue, K., and Mizushima, N. (2008). Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol. Biol. Cell 19, 5360–5372.PubMedCrossRefGoogle Scholar
  28. Jellinger, K.A. (2010). Basic mechanisms of neurodegeneration: a critical update. J. Cell. Mol. Med. 14, 457–487.PubMedCrossRefGoogle Scholar
  29. Johansen, T., and Lamark, T. (2011). Selective autophagy mediated by autophagic adapter proteins. Autophagy 7, 279–296.PubMedCrossRefGoogle Scholar
  30. Jung, H.S., and Lee, M.S. (2010). Role of autophagy in diabetes and mitochondria. Ann. N Y Acad. Sci. 1201, 79–83.PubMedCrossRefGoogle Scholar
  31. Jung, C.H., Jun, C.B., Ro, S.H., Kim, Y.M., Otto, N.M., Cao, J., Kundu, M., and Kim, D.H. (2009). ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992–2003.PubMedCrossRefGoogle Scholar
  32. Jung, C.H., Ro, S.H., Cao, J., Otto, N.M., and Kim, D.H. (2010). mTOR regulation of autophagy. FEBS Lett. 584, 1287–1295.PubMedCrossRefGoogle Scholar
  33. Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., and Yoshimori, T. (2000). LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728.PubMedCrossRefGoogle Scholar
  34. Kabeya, Y., Mizushima, N., Yamamoto, A., Oshitani-Okamoto, S., Ohsumi, Y., and Yoshimori T. (2004). LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J. Cell Sci. 117, 2805–2812.PubMedCrossRefGoogle Scholar
  35. Kamimoto, T., Shoji, S., Hidvegi, T., Mizushima, N., Umebayashi, K., Perlmutter, D.H., and Yoshimori, T. (2006). Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. J. Biol. Chem. 281, 4467–4476.PubMedCrossRefGoogle Scholar
  36. Kaushik, S., Bandyopadhyay, U., Sridhar, S., Kiffin, R., Martinez-Vicente, M. Kon, M., Orenstein, S.J., Wong, E., and Cuervo, A.M. (2011a). Chaperone-mediated autophagy at a glance. J. Cell Sci. 124, 495–499.PubMedCrossRefGoogle Scholar
  37. Kaushik, S., Rodriguez-Navarro, J.A., Arias, E., Kiffin, R., Sahu, S., Schwartz, G.J., Cuervo, A.M., and Singh, R. (2011b). Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab. 14, 173–183.PubMedCrossRefGoogle Scholar
  38. Kawaguchi, Y., Kovacs, J.J., McLaurin, A., Vance, J.M., Ito, A., and Yao, T.P. (2003). The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115, 727–738.PubMedCrossRefGoogle Scholar
  39. Ke, P.Y., and Chen, S.S. (2011). Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro. J. Clin. Invest. 121, 37–56.PubMedCrossRefGoogle Scholar
  40. Kim, J., Kundu, M., Viollet, B., and Guan, K.L. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141.PubMedCrossRefGoogle Scholar
  41. Kirkin, V., Lamark, T., Sou, Y.S., Bjørkøy, G., Nunn, J.L., Bruun, J.A., Shvets, E., McEwan, D.G., Clausen, T.H., Wild, P., et al. (2009). A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol. Cell 33, 505–516.PubMedCrossRefGoogle Scholar
  42. Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., et al. (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884.PubMedCrossRefGoogle Scholar
  43. Kroemer, G., Mariño, G., and Levine, B. (2010). Autophagy and the integrated stress response. Mol. Cell 40, 280–293.PubMedCrossRefGoogle Scholar
  44. Kyei, G.B., Dinkins, C., Davis, A.S., Roberts, E., Singh, S.B., Dong, C., Wu, L., Kominami, E., Ueno, T., Yamamoto, A., et al. (2009). Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages. J. Cell Biol. 186, 255–268.PubMedCrossRefGoogle Scholar
  45. Lamark, T., and Johansen, T. (2012). Aggrephagy: selective disposal of protein aggregates by macroautophagy. Int. J. Cell Biol. 2012, 736905.PubMedGoogle Scholar
  46. Lee, J.Y., Koga, H., Kawaguchi, Y., Tang, W., Wong, E., Gao, Y.S., Pandey, U.B., Kaushik, S., Tresse, E., Lu, J., et al. (2010). HDAC6 controls autophagosome maturation essential for ubiquitinselective quality-control autophagy. EMBO J. 29, 969–980.PubMedCrossRefGoogle Scholar
  47. Levine, B., and Kroemer, G. (2008). Autophagy in the pathogenesis of disease. Cell 132, 27–42.PubMedCrossRefGoogle Scholar
  48. Levine, B., Mizushima, N., and Virgin, H.W. (2011). Autophagy in immunity and inflammation. Nature 469, 323–335.PubMedCrossRefGoogle Scholar
  49. Li, J., Liu, Y., Wang, Z., Liu, K., Wang, Y., Liu, J., Ding, H., and Yuan, Z. (2011). Subversion of cellular autophagy machinery by hepatitis B virus for viral envelopment. J. Virol. 85, 6319–6333.PubMedCrossRefGoogle Scholar
  50. Liang, X.H., Jackson, S., Seaman, M., Brown, K., Kempkes, B., Hibshoosh, H., and Levine, B. (1999). Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676.PubMedCrossRefGoogle Scholar
  51. Liu, K., and Czaja, M.J. (2013). Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ. 20, 3–11.PubMedCrossRefGoogle Scholar
  52. Liu, L., Feng, D., Chen, G., Chen, M., Zheng, Q., Song, P., Ma, Q., Zhu, C., Wang, R., Qi, W., et al. (2012). Mitochondrial outermembrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat. Cell Biol. 14, 177–185.PubMedCrossRefGoogle Scholar
  53. Luciani, A., Villella, V.R., Esposito, S., Brunetti-Pierri, N., Medina, D., Settembre, C., Gavina, M., Pulze, L., Giardino, I., Pettoello-Mantovani, M., et al. (2010). Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat. Cell Biol. 12, 863–875.PubMedCrossRefGoogle Scholar
  54. Ma, J.F., Huang, Y., Chen, S.D., and Halliday, G. (2010). Immunohistochemical evidence for macroautophagy in neurones and endothelial cells in Alzheimer’s disease. Neuropathol. Appl. Neurobiol. 36, 312–319.PubMedCrossRefGoogle Scholar
  55. Maiuri, M.C., Zalckvar, E., Kimchi, A., and Kroemer, G. (2007). Selfeating and self-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 8, 741–752.PubMedCrossRefGoogle Scholar
  56. Marciniak, S.J., and Lomas, D.A. (2010). Alpha1-antitrypsin deficiency and autophagy. N. Engl. J. Med. 363, 1863–1864.PubMedCrossRefGoogle Scholar
  57. Martinez-Vicente, M., Talloczy, Z., Wong, E., Tang, G., Koga, H., Kaushik, S., de Vries, R., Arias, E., Harris, S., Sulzer, D., et al. (2010). Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat. Neurosci. 13, 567–576.PubMedCrossRefGoogle Scholar
  58. Metcalf, D.J., García-Arencibia, M., Hochfeld, W.E., and Rubinsztein, D.C. (2012). Autophagy and misfolded proteins in neurodegeneration. Exp. Neurol. 238, 22–28.PubMedCrossRefGoogle Scholar
  59. Mihaylova, M.M., and Shaw, R.J. (2011). The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13, 1016–1023.PubMedCrossRefGoogle Scholar
  60. Min, T., Bodas, M., Mazur, S., and Vij, N. (2011). Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema. J. Mol. Med. (Berl.) 89, 577–593.CrossRefGoogle Scholar
  61. Mizushima, N. (2010). The role of the Atg1/ULK1 complex in autophagy regulation. Curr. Opin. Cell Biol. 22, 132–139.PubMedCrossRefGoogle Scholar
  62. Mizushima, N., and Komatsu, M. (2011). Autophagy: renovation of cells and tissues. Cell 147, 728–741.PubMedCrossRefGoogle Scholar
  63. Mizushima, N., Levine, B., Cuervo, A.M., and Klionsky, D.J. (2008). Autophagy fights disease through cellular self-digestion. Nature 451, 1069–2075.PubMedCrossRefGoogle Scholar
  64. Mizushima, N., Yoshimori, T., and Levine, B. (2010). Methods in mammalian autophagy research. Cell 140, 313–326.PubMedCrossRefGoogle Scholar
  65. Mornex, J.F., Chytil-Weir, A., Martinet, Y., Courtney, M., LeCocq, J.P., and Crystal, R.G. (1986). Expression of the alpha-1-antitrypsin gene in mononuclear phagocytes of normal and alpha-1-antitrypsin-deficient individuals. J. Clin. Invest. 77, 1952–1961.PubMedCrossRefGoogle Scholar
  66. Morris, H.R. (2005). Genetics of Parkinson’s disease. Ann. Med. 37, 86–96.PubMedCrossRefGoogle Scholar
  67. Nakahira, K., Haspel, J.A., Rathinam, V.A., Lee, S.J., Dolinay, T., Lam, H.C., Englert, J.A., Rabinovitch, M., Cernadas, M., Kim, H.P., et al. (2011). Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230.PubMedCrossRefGoogle Scholar
  68. Narendra, D., Tanaka, A., Suen, D.F., and Youle, R.J. (2008). Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803.PubMedCrossRefGoogle Scholar
  69. Orvedahl, A., Sumpter, R., Xiao, G., Ng, A., Zou, Z., Tang, Y., Narimatsu, M., Gilpin, C., Sun, Q., Roth, M., et al. (2011). Imagebased genome-wide siRNA screen identifies selective autophagy factors. Nature 480, 113–117.PubMedCrossRefGoogle Scholar
  70. Pattingre, S., Tassa, A., Qu, X., Garuti, R., Liang, X.H., Mizushima, N., Packer, M., Schneider, M.D., and Levine, B. (2005). Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939.PubMedCrossRefGoogle Scholar
  71. Pickford, F., Masliah, E., Britschgi, M., Lucin, K., Narasimhan, R., Jaeger, P.A., Small, S., Spencer, B., Rockenstein, E., and Levine, B. (2008). The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Invest. 118, 2190.PubMedGoogle Scholar
  72. Ranes, J., and Stoller, J.K. (2005). A review of alpha-1 antitrypsin deficiency. Semin. Respir. Crit. Care Med. 26, 154–166.PubMedCrossRefGoogle Scholar
  73. Ravikumar, B., Duden, R., and Rubinsztein, D.C. (2002). Aggregateprone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 107–117CrossRefGoogle Scholar
  74. Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, L.G., Scaravilli, F., Easton, D.F., Duden, R., O’Kane, C.J., et al. (2004). Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595.PubMedCrossRefGoogle Scholar
  75. Ravikumar, B., Sarkar, S., Davies, J.E., Futter, M., Garcia-Arencibia, M., Green-Thompson, Z.W., Jimenez-Sanchez, M., Korolchuk, V.I., Lichtenberg, M., Luo, S., et al. (2010). Regulation of mammalian autophagy in physiology and pathophysiology. Physiol. Rev. 90, 1383–1435.PubMedCrossRefGoogle Scholar
  76. Rubinsztein, D.C., Codogno, P., and Levine, B. (2012). Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709–730.PubMedCrossRefGoogle Scholar
  77. Santambrogio, L., and Cuervo, A.M. (2011). Chasing the elusive mammalian microautophagy. Autophagy 7, 652–654.PubMedCrossRefGoogle Scholar
  78. Satoo, K., Noda, N.N., Kumeta, H., Fujioka, Y., Mizushima, N., Ohsumi, Y., and Inagaki, F. (2009). The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy. EMBO J. 28, 1341–1350.PubMedCrossRefGoogle Scholar
  79. Schaeffer, V., Lavenir, I., Ozcelik, S., Tolnay, M., Winkler, D.T., and Goedert, M. (2012). Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain 135, 2169–2177.PubMedCrossRefGoogle Scholar
  80. Schreiber, A., and Peter, M. (2013). Substrate recognition in selective autophagy and the ubiquitin-proteasome system. Biochim. Biophys. Acta pii: S0167-4889(13)00120-1.Google Scholar
  81. Shaid, S., Brandts, C.H., Serve, H., and Dikic, I. (2013). Ubiquitination and selective autophagy. Cell Death Differ. 20, 21–30.PubMedCrossRefGoogle Scholar
  82. Shibata, M., Lu, T., Furuya, T., Degterev, A., Mizushima, N., Yoshimori, T., MacDonald, M., Yankner, B., and Yuan, J. (2006). Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J. Biol. Chem. 281, 14474–14485.PubMedCrossRefGoogle Scholar
  83. Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A.M., and Czaja, M.J. (2009a). Autophagy regulates lipid metabolism. Nature 458, 1131–11135.PubMedCrossRefGoogle Scholar
  84. Singh, R., Xiang, Y., Wang, Y., Baikati, K., Cuervo, A.M., Luu, Y.K., Tang, Y., Pessin, J.E., Schwartz, G.J., and Czaja, M.J. (2009b). Autophagy regulates adipose mass and differentiation in mice. J. Clin. Invest. 119, 3329–3339.PubMedCrossRefGoogle Scholar
  85. Spencer, B., Potkar, R., Trejo, M., Rockenstein, E., Patrick, C., Gindi, R., Adame, A., Wyss-Coray, T., and Masliah, E. (2009). Beclin1 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.PubMedCrossRefGoogle Scholar
  86. Starr, T., Child, R., Wehrly, T.D., Hansen, B., Hwang, S., López-Otin, C., Virgin, H.W., and Celli, J. (2012). Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle. Cell Host Microbe 11, 33–45.PubMedCrossRefGoogle Scholar
  87. Thurston, T.L., Ryzhakov, G., Bloor, S., von Muhlinen, N., and Randow, F. (2009). The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat. Immunol. 10, 1215–1221.PubMedCrossRefGoogle Scholar
  88. Tian, Y., Sir, D., Kuo, C.F., Ann, D.K., and Ou, J.H. (2011). Autophagy required for hepatitis B virus replication in transgenic mice. J. Virol. 85, 13453–13456.PubMedCrossRefGoogle Scholar
  89. Trancikova, A., Tsika, E., and Moore, D.J. (2012). Mitochondrial dysfunction in genetic animal models of Parkinson’s disease. Antioxid. Redox Signal. 216, 896–919.CrossRefGoogle Scholar
  90. Vander Haar, E., Lee, S.I., Bandhakavi, S., Griffin, T.J., and Kim, D.H. (2007). Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9, 316–323.CrossRefGoogle Scholar
  91. Vives-Bauza, C., Zhou, C., Huang, Y., Cui, M., de Vries, R.L., Kim, J., May, J., Tocilescu, M.A., Liu, W., Ko, H.S., et al. (2010). PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl. Acad. Sci. USA 107, 378–383.PubMedCrossRefGoogle Scholar
  92. Wang, R.C., Wei, Y., An, Z., Zou, Z., Xiao, G., Bhagat, G., White, M., Reichelt, J., and Levine, B. (2012). Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338, 956–959.PubMedCrossRefGoogle Scholar
  93. Wild, P., Farhan, H., McEwan, D.G., Wagner, S., Rogov, V.V., Brady, N.R., Richter, B., Korac, J., Waidmann, O., Choudhary, C., et al. (2011). Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228–233.PubMedCrossRefGoogle Scholar
  94. Winslow, A.R., Chen, C.W., Corrochano, S., Acevedo-Arozena, A., Gordon, D.E., Peden, A.A., Lichtenberg, M., Menzies, F.M., Ravikumar, B., Imarisio, S., et al. (2010). α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J. Cell Biol. 190, 1023–1037.PubMedCrossRefGoogle Scholar
  95. Wong, E., and Cuervo, A.M. (2010). Autophagy gone awry in neurodegenerative diseases. Nat. Neurosci. 13, 805–811.PubMedCrossRefGoogle Scholar
  96. Wong, P.M., Puente, C., Ganley, I.G., and Jiang, X. (2013). The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 9, 124–137.PubMedCrossRefGoogle Scholar
  97. Yamamoto, A., and Simonsen, A. (2011). The elimination of accumulated and aggregated proteins: a role for aggrephagy in neurodegeneration. Neurobiol. Dis. 43, 17–28.PubMedCrossRefGoogle Scholar
  98. Yamamoto, H., Kakuta, S., Watanabe, T.M., Kitamura, A., Sekito, T., Kondo-Kakuta, C., Ichikawa, R., Kinjo, M., and Ohsumi, Y. (2012). Atg9 vesicles are an important membrane source during early steps of autophagosome formation. J. Cell Biol. 198, 219–233.PubMedCrossRefGoogle Scholar
  99. Yang, Z., and Klionsky, D.J. (2010a). Eaten alive: a history of macroautophagy. Nat. Cell Biol. 12, 814–822.PubMedCrossRefGoogle Scholar
  100. Yang, Z., and Klionsky, D.J. (2010b). Mammalian autophagy: core molecular machinery and signaling regulation. Curr. Opin. Cell Biol. 22, 124–131.PubMedCrossRefGoogle Scholar
  101. Yang, L., Li, P., Fu, S., Calay, E.S., and Hotamisligil, G.S. (2010). Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11, 467–478.PubMedCrossRefGoogle Scholar
  102. Yano, T., and Kurata, S. (2011). Intracellular recognition of pathogens and autophagy as an innate immune host defence. J. Biochem. 150, 143–149.PubMedCrossRefGoogle Scholar
  103. Youle, R.J., and Narendra, D.P. (2011). Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14.PubMedCrossRefGoogle Scholar
  104. Young, A.R., Chan, E.Y., Hu, X.W., Köchl, R., Crawshaw, S.G., High, S., Hailey, D.W., Lippincott-Schwartz, J., and Tooze, S.A. (2006). Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J. Cell Sci. 119, 3888–3900.PubMedCrossRefGoogle Scholar
  105. Yu, W.H., Cuervo, A.M., Kumar, A., Peterhoff, C.M., Schmidt, S.D., Lee, J.H., Mohan, P.S., Mercken, M., Farmery, M.R., Tjernberg, L.O., et al. (2005). Macroautophagy-a novel Beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J. Cell Biol. 171, 87–98.PubMedCrossRefGoogle Scholar
  106. Zhang, H., Bosch-Marce, M., Shimoda, L.A., Tan, Y.S., Baek, J.H., Wesley, J.B., Gonzalez, F.J., and Semenza, G.L. (2008). Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J. Biol. Chem. 283, 10892–10903.PubMedCrossRefGoogle Scholar
  107. Zhou, Z., Wu, S., Li, X., Xue, Z., and Tong, J. (2010). Rapamycin induces autophagy and exacerbates metabolism associated complications in a mouse model of type 1 diabetes. Indian J. Exp. Biol. 48, 31–38.PubMedGoogle Scholar

Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2013

Authors and Affiliations

  • Stefan W. Ryter
    • 1
  • Suzanne M. Cloonan
    • 1
  • Augustine M. K. Choi
    • 1
  1. 1.Pulmonary and Critical Care Medicine, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations