Autophagy: Process and function

Genes and Development

Volumn 21, Issue 22, 2007, Pages 2861-2873

  Mizushima, Noboru ^a,b  

^a TOKYO MEDICAL AND DENTAL UNIVERSITY   (Japan)

^b JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

Author keywords

Amino acids; Autophagosome; Autophagy; Degradation; Lysosome

Indexed keywords

AMINO ACID SEQUENCE; AUTOPHAGY; CELL FUNCTION; CELL ORGANELLE; CYTOPLASM; LYSOSOME MEMBRANE; MACROMOLECULE; MEMBRANE FORMATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN TRANSPORT; REVIEW;

ANIMALS; AUTOPHAGY; ENDOSOMES; FUNGAL PROTEINS; INTRACELLULAR MEMBRANES; LYSOSOMES; MEMBRANE FUSION; MODELS, BIOLOGICAL; PHAGOSOMES; PROTEIN BINDING; PROTEIN TRANSPORT; SACCHAROMYCES CEREVISIAE; SACCHAROMYCES CEREVISIAE PROTEINS;

EID: 36249025723     PISSN: 08909369     EISSN: 15495477     Source Type: Journal    
DOI: 10.1101/gad.1599207     Document Type: Review

References (159)

1. Adhami, F., Liao, G., Morozov, Y.M., Schloemer, A., Schmithorst, V.J., Lorenz, J.N., Dunn, R.S., Vorhees, C.V., Wills-Karp, M., Degen, J.L., et al. 2006. Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am. J. Pathol. 169: 566-583.
2. Amaravadi, R.K., Yu, D., Lum, J.J., Bui, T., Christophorou, M.A., Evan, G.I., Thomas-Tikhonenko, A., and Thompson, C.B. 2007. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 117: 326-336.
3. Amer, A.O. and Swanson, M.S. 2005. Autophagy is an immediate macrophage response to Legionella pneumophila. Cell. Microbiol. 7: 765-778.
4. Anglade, P., Vyas, S., Javoy-Agid, F., Herrero, M.T., Michel, P.P., Marquez, J., Mouatt-Prigent, A., Ruberg, M., Hirsch, E.C., and Agid, Y. 1997. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol. Histopathol. 12: 25-31.
5. Berg, T.O., Fengsrud, M., Stromhaug, P.E., Berg, T., and Seglen, P.O. 1998. Isolation and characterization of rat liver amphisomes. Evidence for fusion of autophagosomes with both early and late endosomes. J. Biol. Chem. 273: 21883-21892.
6. Bernales, S., McDonald, K.L., and Walter, P. 2006. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4: e423. doi: 10.1371/journal.pbio.0040423.
7. Beron, W., Gutierrez, M.G., Rabinovitch, M., and Colombo, M.I. 2002. Coxiella burnetii localizes in a Rab7-labeled compartment with autophagic characteristics. Infect. Immun. 70: 5816-5821.
8. Bjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., ∅vervatn, A., Stenmark, H., and Johansen, T. 2005. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171: 603-614.
9. Bohensky, J., Shapiro, I.M., Leshinsky, S., Terkhorn, S.P., Adams, C.S., and Srinivas, V. 2007. HIF-1 regulation of chondrocyte apoptosis: Induction of the autophagic pathway. Autophagy 3: 207-214.
10. Brabec-Zaruba, M., Berka, U., Blaas, D., and Fuchs, R. 2007. Induction of autophagy does not affect human Rhinovirus 2 production. J. Virol. 81: 10815-10817.
11. Byfield, M.P., Murray, J.T., and Backer, J.M. 2005. hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J. Biol. Chem. 280: 33076-33082.
12. Cataldo, A.M., Hamilton, D.J., Barnett, J.L., Paskevich, P.A., and Nixon, R.A. 1996. Properties of the endosomal-lysosomal system in the human central nervous system: Disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease. J. Neurosci. 16: 186-199.
13. Codogno, P. and Meijer, A.J. 2005. Autophagy and signaling: Their role in cell survival and cell death. Cell Death Differ. 12 (Suppl. 2): 1509-1518.
14. Crighton, D., Wilkinson, S., O'Prey, J., Syed, N., Smith, P., Harrison, P.R., Gasco, M., Garrone, O., Crook, T., and Ryan, K.M. 2006. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126: 121-134.
15. Criollo, A., Maiuri, M.C., Tasdemir, E., Vitale, I., Fiebig, A.A., Andrews, D., Molgo, J., Diaz, J., Lavandero, S., Harper, F., et al. 2007. Regulation of autophagy by the inositol trisphosphate receptor. Cell Death Differ. 14: 1029-1039.
16. Cuervo, A.M. 2004. Autophagy: In sickness and in health. Trends Cell Biol. 14: 70-77.
17. Daido, S., Kanzawa, T., Yamamoto, A., Takeuchi, H., Kondo, Y., and Kondo, S. 2004. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res. 64: 4286-4293.
18. Debnath, J., Baehrecke, E.H., and Kroemer, G. 2005. Does autophagy contribute to cell death? Autophagy 1: 66-74.
19. Degenhardt, K., Mathew, R., Beaudoin, B., Bray, K., Anderson, D., Chen, G., Mukherjee, C., Shi, Y., Gelinas, C., Fan, Y., et al. 2006. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10: 51-64.
20. Demarchi, F., Bertoli, C., Copetti, T., Tanida, I., Brancolini, C., Eskelinen, E.-L., and Schneider, C. 2006. Calpain is required for macroautophagy in mammalian cells. J. Cell Biol. 175: 595-605.
21. de Waal, E.J., Vreeling-Sindelarova, H., Schellens, J.P., Houtkooper, J.M., and James, J. 1986. Quantitative changes in the lysosomal vacuolar system of rat hepatocytes during short-term starvation. A morphometric analysis with special reference to macro- and microautophagy. Cell Tissue Res. 243: 641-648.
22. Ding, W.X., Ni, H.M., Gao, W., Hou, Y.F., Melan, M.A., Chen, X., Stolz, D.B., Shao, Z.M., and Yin, X.M. 2007. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J. Biol. Chem. 282: 4702-4710.
23. Djavaheri-Mergny, M., Amelotti, M., Mathieu, J., Besancon, F., Bauvy, C., Souquere, S., Pierron, G., and Codogno, P. 2006. NF-κB activation represses tumor necrosis factor-α-induced autophagy. J. Biol. Chem. 281: 30373-30382.
24. Dorn, B.R., Dunn Jr., W.A., and Progulske-Fox, A. 2001. Porphyromonas gingivalis traffics to autophagosomes in human coronary artery endothelial cells. Infect. Immun. 69: 5698-5708.
25. Edinger, A.L. and Thompson, C.B. 2004. Death by design: Apoptosis, necrosis and autophagy. Curr. Opin. Cell Biol. 16: 663-669.
26. Epple, U.D., Suriapranata, I., Eskelinen, E.-L., and Thumm, M. 2001. Aut5/Cvt17p, a putative lipase essential for disintegration of autophagic bodies inside the vacuole. J. Bacteriol. 183: 5942-5955.
27. Gordon, P.B. and Seglen, P.O. 1988. Prelysosomal convergence of autophagic and endocytic pathways. Biochem. Biophys. Res. Commun. 151: 40-47.
28. Gutierrez, M.G., Master, S.S., Singh, S.B., Taylor, G.A., Colombo, M.I., and Deretic, V. 2004. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119: 753-766.
29. Hampe, J., Franke, A., Rosenstiel, P., Till, A., Teuber, M., Huse, K., Albrecht, M., Mayr, G., De La Vega, F.M., Briggs, J., et al. 2007. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39: 207-211.
30. 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 441: 885-889.
31. Hippert, M.M., O'Toole, P.S., and Thorburn, A. 2006. Autophagy in cancer: Good, bad, or both? Cancer Res. 66: 9349-9351.
32. Hoyer-Hansen, M., Bastholm, L., Szyniarowski, P., Campanella, M., Szabadkai, G., Farkas, T., Bianchi, K., Fehrenbacher, N., Elling, F., Rizzuto, R., et al. 2007. Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-β, and Bcl-2. Mol. Cell 25: 193-205.
33. Ionov, Y., Nowak, N., Perucho, M., Markowitz, S., and Cowell, J.K. 2004. Manipulation of nonsense mediated decay identifies gene mutations in colon cancer cells with microsatellite instability. Oncogene 23: 639-645.
34. Iwata, J., Ezaki, J., Komatsu, M., Yokota, S., Ueno, T., Tanida, I., Chiba, T., Tanaka, K., and Kominami, E. 2006. Excess peroxisomes are degraded by autophagic machinery in mammals. J. Biol. Chem. 281: 4035-4041.
35. Jackson, W.T., Giddings Jr., T.H., Taylor, M.P., Mulinyawe, S., Rabinovitch, M., Kopito, R.R., and Kirkegaard, K. 2005. Subversion of cellular autophagosomal machinery by RNA viruses. PLoS Biol. 3: e156. doi: 10.1371/journal.pbio.0030156.
36. Jin, S. and White, E. 2007. Role of autophagy in cancer: Management of metabolic stress. Autophagy 3: 28-31.
37. Juhasz, G., Csikos, G., Sinka, R., Erdelyi, M., and Sass, M. 2003. The Drosophila homolog of Aut1 is essential for autophagy and development. FEBS Lett. 543: 154-158.
38. 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.
39. Kabeya, Y., Kawamata, T., Suzuki, K., and Ohsumi, Y. 2007. Cis1/Atg31 is required for autophagosome formation in Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 356: 405-410.
40. Kanazawa, T., Taneike, I., Akaishi, R., Yoshizawa, F., Furuya, N., Fujimura, S., and Kadowaki, M. 2004. Amino acids and insulin control autophagic proteolysis through different signaling pathways in relation to mTOR in isolated rat hepatocytes. J. Biol. Chem. 279: 8452-8459.
41. Karantza-Wadsworth, V., Patel, S., Kravchuk, O., Chen, G., Mathew, R., Jin, S., and White, E. 2007. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes & Dev. 21: 1621-1635.
42. Kawai, T. and Akira, S. 2006. TLR signaling. Cell Death Differ. 13: 816-825.
43. Kawamata, T., Kamada, Y., Suzuki, K., Kuboshima, N., Akimatsu, H., Ota, S., Ohsumi, M., and Ohsumi, Y. 2005. Characterization of a novel autophagy-specific gene, ATG29. Biochem. Biophys. Res. Commun. 338: 1884-1889.
44. Kihara, A., Noda, T., Ishihara, N., and Ohsumi, Y. 2001. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J. Cell Biol. 152: 519-530.
45. Kim, J., Huang, W.-P., and Klionsky, D.J. 2001. Membrane recruitment of Aut7p in the autophagy and cytoplasm to vacuole targeting pathways requires Aut1p, Aut2p, and autophagy conjugation complex. J. Cell Biol. 152: 51-64.
46. Kim, I., Rodriguez-Enriquez, S., and Lemasters, J.J. 2007. Selective degradation of mitochondria by mitophagy. Arch. Biochem. Biophys. 462: 245-253.
47. Kirkegaard, K., Taylor, M.P., and Jackson, W.T. 2004. Cellular autophagy: Surrender, avoidance and subversion by microorganisms. Nat. Rev. Microbiol. 2: 301-314.
48. Klionsky, D.J. 2005. The molecular machinery of autophagy: Unanswered questions. J. Cell Sci. 118: 7-18.
49. Klionsky, D.J. 2007. Autophagy: From phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol. doi: 10.1038/nrm2245.
50. Klionsky, D.J. and Ohsumi, Y. 1999. Vacuolar import of proteins and organelles from the cytoplasm. Annu. Rev. Cell Dev. Biol. 15: 1-32.
51. Klionsky, D.J., Cregg, J.M., Dunn Jr., W.A., Emr, S.D., Sakai, Y., Sandoval, I.V., Sibirny, A., Subramani, S., Thumm, M., Veenhuis, M., et al. 2003. A unified nomenclature for yeast autophagy-related genes. Dev. Cell 5: 539-545.
52. Klionsky, D.J., Cuervo, A.M., and Seglen, P.O. 2007. Methods for monitoring autophagy from yeast to human. Autophagy 3: 181-206.
53. Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., et al. 2005. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169: 425-434.
54. Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J.I., 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.
55. Kouroku, Y., Fujita, E., Tanida, I., Ueno, T., Isoai, A., Kumagai, H., Ogawa, S., Kaufman, R.J., Kominami, E., and Momoi, T. 2007. ER stress (PERK/eIF2α phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. 14: 230-239.
56. Kroemer, G., El-Deiry, W.S., Golstein, P., Peter, M.E., Vaux, D., Vandenabeele, P., Zhivotovsky, B., Blagosklonny, M.V., Malorni, W., Knight, R.A., et al. 2005. Classification of cell death: Recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ. 12 (Suppl. 2): 1463-1467.
57. Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., and Mizushima, N. 2004. The role of autophagy during the early neonatal starvation period. Nature 432: 1032-1036.
58. Laurin, N., Brown, J.P., Morissette, J., and Raymond, V. 2002. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am. J. Hum. Genet. 70: 1582-1588.
59. Lee, H.K., Lund, J.M., Ramanathan, B., Mizushima, N., and Iwasaki, A. 2007. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315: 1398-1401.
60. Levine, B. 2007. Cell biology: Autophagy and cancer. Nature 446: 745-747.
61. Levine, B. and Klionsky, D.J. 2004. Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Dev. Cell 6: 463-477.
62. Liang, X.H., Kleeman, L.K., Jiang, H.H., Gordon, G., Goldman, J.E., Berry, G., Herman, B., and Levine, B. 1998. Protection against fatal Sindbis virus encephalitis by Beclin, a novel Bcl-2-interacting protein. J. Virol. 72: 8586-8596.
63. 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.
64. Liang, C., Feng, P., Ku, B., Dotan, I., Canaani, D., Oh, B.H., and Jung, J.U. 2006. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat. Cell Biol. 8: 688-699.
65. Liang, J., Shao, S.H., Xu, Z.X., Hennessy, B., Ding, Z., Larrea, M., Kondo, S., Dumont, D.J., Gutterman, J.U., Walker, C.L., et al. 2007. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat. Cell Biol. 9: 218-224.
66. Liu, Y., Schiff, M., Czymmek, K., Talloczy, Z., Levine, B., and Dinesh-Kumar, S.P. 2005. Autophagy regulates programmed cell death during the plant innate immune response. Cell 121: 567-577.
67. Luiken, J.J., van den Berg, M., Heikoop, J.C., and Meijer, A.J. 1992. Autophagic degradation of peroxisomes in isolated rat hepatocytes. FEBS Lett. 304: 93-97.
68. Lum, J.J., Bauer, D.E., Kong, M., Harris, M.H., Li, C., Lindsten, T., and Thompson, C.B. 2005a. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120: 237-248.
69. Lum, J.J., Deberardinis, R.J., and Thompson, C.B. 2005b. Autophagy in metazoans: Cell survival in the land of plenty. Nat. Rev. Mol. Cell Biol. 6: 439-448.
70. Maiuri, M.C., Le Toumelin, G., Criollo, A., Rain, J.C., Gautier, F., Juin, P., Tasdemir, E., Pierron, G., Troulinaki, K., Tavernarakis, N., et al. 2007. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J. 26: 2527-2539.
71. Maria Fimia, G., Stoykova, A., Romagnoli, A., Giunta, L., Di Bartolomeo, S., Nardacci, R., Corazzari, M., Fuoco, C., Ucar, A., Schwartz, P., et al. 2007. Ambra1 regulates autophagy and development of the nervous system. Nature 447: 1121-1125.
72. Marino, G., Salvador-Montoliu, N., Fueyo, A., Knecht, E., Mizushima, N., and Lopez-Otin, C. 2007. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J. Biol. Chem. 282: 18573-18583.
73. Martinez-Vicente, M. and Cuervo, A.M. 2007. Autophagy and neurodegeneration: When the cleaning crew goes on strike. Lancet Neurol. 6: 352-361.
74. Mathew, R., Kongara, S., Beaudoin, B., Karp, C.M., Bray, K., Degenhardt, K., Chen, G., Jin, S., and White, E. 2007. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes & Dev. 21: 1367-1381.
75. Matsui, Y., Takagi, H., Qu, X., Abdellatif, M., Sakoda, H., Asano, T., Levine, B., and Sadoshima, J. 2007. 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.
76. Melendez, A., Tallóczy, Z., Seaman, M., Eskelinen, E.-L., Hall, D.H., and Levine, B. 2003. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301: 1387-1391.
77. Meley, D., Bauvy, C., Houben-Weerts, J.H., Dubbelhuis, P.F., Helmond, M.T., Codogno, P., and Meijer, A.J. 2006. AMP-activated protein kinase and the regulation of autophagic proteolysis. J. Biol. Chem. 281: 34870-34879.
78. Mills, K.R., Reginato, M., Debnath, J., Queenan, B., and Brugge, J.S. 2004. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc. Natl. Acad. Sci. 101: 3438-3443.
79. Mizushima, N. 2005. The pleiotropic role of autophagy: From protein metabolism to bactericide. Cell Death Differ. 12 (Suppl. 2): 1535-1541.
80. Mizushima, N. and Klionsky, D.J. 2007. Protein turnover via autophagy: Implications for metabolism. Annu. Rev. Nutr. 27: 19-40.
81. Mizushima, N. and Yoshimori, T. 2007. How to interpret LC3 immunoblotting. Autophagy 3: 542-545.
82. Mizushima, N., Kuma, A., Kobayashi, Y., Yamamoto, A., Matsubae, M., Takao, T., Natsume, T., Ohsumi, Y., and Yoshimori, T. 2003. Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J. Cell Sci. 116: 1679-1688.
83. Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T., and Ohsumi, Y. 2004. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15: 1101-1111.
84. Mordier, S., Deval, C., Bechet, D., Tassa, A., and Ferrara, M. 2000. Leucine limitation induces autophagy and activation of lysosome-dependent proteolysis in C2C12 myotubes through a mammalian target of rapamycin- independent signaling pathway. J. Biol. Chem. 275: 29900-29906.
85. Moriyasu, Y. and Ohsumi, Y. 1996. Autophagy in tobacco suspension-cultured cells in response to sucrose starvation. Plant Physiol. 111: 1233-1241.
86. Mortimore, G.E. and Pösö, A.R. 1987. Intracellular protein catabolism and its control during nutrient deprivation and supply. Annu. Rev. Nutr. 7: 539-564.
87. Mortimore, G.E., Hutson, N.J., and Surmacz, C.A. 1983. Quantitative correlation between proteolysis and macro- and microautophagy in mouse hepatocytes during starvation and refeeding. Proc. Natl. Acad. Sci. 80: 2179-2183.
88. Moscat, J., Diaz-Meco, M.T., and Wooten, M.W. 2007. Signal integration and diversification through the p62 scaffold protein. Trends Biochem. Sci. 32: 95-100.
89. Nakagawa, I., Amano, A., Mizushima, N., Yamamoto, A., Yamaguchi, H., Kamimoto, T., Nara, A., Funao, J., Nakata, M., Tsuda, K., et al. 2004. Autophagy defends cells against invading group A Streptococcus. Science 306: 1037-1040.
90. Nakai, A., Yamaguchi, O., Takeda, T., Higuchi, Y., Hikoso, S., Taniike, M., Omiya, S., Mizote, I., Matsumura, Y., Asahi, M., et al. 2007. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat. Med. 13: 619-624.
91. Nakatogawa, H., Ichimura, Y., and Ohsumi, Y. 2007. Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130: 165-178.
92. Newsholme, E.A., Crabtree, B., and Ardawi, M.S. 1985. Glutamine metabolism in lymphocytes: Its biochemical, physiological and clinical importance. Q. J. Exp. Physiol. 70: 473-489.
93. Nobukuni, T., Joaquin, M., Roccio, M., Dann, S.G., Kim, S.Y., Gulati, P., Byfield, M.P., Backer, J.M., Natt, F., Bos, J.L., et al. 2005. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc. Natl. Acad. Sci. 102: 14238-14243.
94. Noda, T. and Ohsumi, Y. 1998. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J. Biol. Chem. 273: 3963-3966.
95. Oberstein, A., Jeffrey, P.D., and Shi, Y. 2007. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J. Biol. Chem. 282: 13123-13132.
96. Ogata, M., Hino, S., Saito, A., Morikawa, K., Kondo, S., Kanemoto, S., Murakami, T., Taniguchi, M., Tanii, I., Yoshinaga, K., et al. 2006. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. 26: 9220-9231.
97. Ogawa, M., Yoshimori, T., Suzuki, T., Sagara, H., Mizushima, N., and Sasakawa, C. 2005. Escape of intracellular Shigella from autophagy. Science 307: 727-731.
98. Okamoto, K., Hirai, S., Iizuka, T., Yanagisawa, T., and Watanabe, M. 1991. Reexamination of granulovacuolar degeneration. Acta Neuropathol. (Berl.) 82: 340-345.
99. Onodera, J. and Ohsumi, Y. 2004. Ald6p is a preferred target for autophagy in yeast, Saccharomyces cerevisiae. J. Biol. Chem. 279: 16071-16076.
100. Onodera, J. and Ohsumi, Y. 2005. Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation. J. Biol. Chem. 280: 31582-31586.
101. Otto, G.P., Wu, M.Y., Kazgan, N., Anderson, O.R., and Kessin, R.H. 2003. Macroautophagy is required for multicellular development of the social amoeba Dictyostelium discoideum. J. Biol. Chem. 278: 17636-17645.
102. Palou, A., Remesar, X., Arola, L., Herrera, E., and Alemany, M. 1981. Metabolic effects of short term food deprivation in the rat. Horm. Metab. Res. 13: 326-330.
103. Pankiv, S., Hoyvarde Clausen, T., Lamark, T., Brech, A., Bruun, J.A., Outzen, H., Øvervatn, A., Bjørkøy, G., and Johansen, T. 2007. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282: 24131-24145.
104. Parkes, M., Barrett, J.C., Prescott, N.J., Tremelling, M., Anderson, C.A., Fisher, S.A., Roberts, R.G., Nimmo, E.R., Cummings, F.R., Soars, D., et al. 2007. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39: 830-832.
105. 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.
106. Petersen, A., Larsen, K.E., Behr, G.G., Romero, N., Przedborski, S., Brundin, P., and Sulzer, D. 2001. Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum. Mol. Genet. 10: 1243-1254.
107. Pfeifer, U. 1978. Inhibition by insulin of the formation of autophagic vacuoles in rat liver. A morphometric approach to the kinetics of intracellular degradation by autophagy. J. Cell Biol. 78: 152-167.
108. Pizarro-Cerda, J., Moreno, E., Sanguedolce, V., Mege, J.L., and Gorvel, J.P. 1998. Virulent Brucella abortus prevents lysosome fusion and is distributed within autophagosome-like compartments. Infect. Immun. 66: 2387-2392.
109. Prentice, E., Jerome, W.G., Yoshimori, T., Mizushima, N., and Denison, M.R. 2004. Coronavirus replication complex formation utilizes components of cellular autophagy. J. Biol. Chem. 279: 10136-10141.
110. Pua, H.H., Dzhagalov, I., Chuck, M., Mizushima, N., and He, Y.W. 2007. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 204: 25-31.
111. Pyo, J.O., Jang, M.H., Kwon, Y.K., Lee, H.J., Jun, J.I., Woo, H.N., Cho, D.H., Choi, B., Lee, H., Kim, J.H., et al. 2005. Essential Roles of Atg5 and FADD in autophagic cell death: Dissection of autophagic cell death into vacuole formation and cell death. J. Biol. Chem. 280: 20722-20729.
112. Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., Rosen, J., Eskelinen, E.-L., Mizushima, N., Ohsumi, Y., et al. 2003. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112: 1809-1820.
113. Qu, X., Zou, Z., Sun, Q., Luby-Phelps, K., Cheng, P., Hogan, R.N., Gilpin, C., and Levine, B. 2007. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128: 931-946.
114. Ravikumar, B., Duden, R., and Rubinsztein, D.C. 2002. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11: 1107-1117.
115. 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.
116. Reef, S., Zalckvar, E., Shifman, O., Bialik, S., Sabanay, H., Oren, M., and Kimchi, A. 2006. A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death. Mol. Cell 22: 463-475.
117. Rioux, J.D., Xavier, R.J., Taylor, K.D., Silverberg, M.S., Goyette, P., Huett, A., Green, T., Kuballa, P., Barmada, M.M., Datta, L.W., et al. 2007. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39: 596-604.
118. Rubinsztein, D.C. 2006. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443: 780-786.
119. Rusten, T.E., Lindmo, K., Juhasz, G., Sass, M., Seglen, P.O., Brech, A., and Stenmark, H. 2004. Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway. Dev. Cell 7: 179-192.
120. Sagné, C., Agulhon, C., Ravassard, P., Darmon, M., Hamon, M., El Mestikawy, S., Gasnier, B., and Giros, B. 2001. Identification and characterization of a lysosomal transporter for small neutral amino acids. Proc. Natl. Acad. Sci. 98: 7206-7211.
121. Sakai, Y., Koller, A., Rangell, L.K., Keller, G.A., and Subramani, S. 1998. Peroxisome degradation by microautophagy in Pichia pastoris: Identification of specific steps and morphological intermediates. J. Cell Biol. 141: 625-636.
122. Sarkar, S., Floto, R.A., Berger, Z., Imarisio, S., Cordenier, A., Pasco, M., Cook, L.J., and Rubinsztein, D.C. 2005. Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170: 1101-1111.
123. Sarkar, S., Perlstein, E.O., Imarisio, S., Pineau, S., Cordenier, A., Maglathlin, R.L., Webster, J.A., Lewis, T.A., O'Kane, C.J., Schreiber, S.L., et al. 2007. Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat. Chem. Biol. 3: 331-338.
124. Scherz-Shouval, R., Shvets, E., Fass, E., Shorer, H., Gil, L., and Elazar, Z. 2007. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 26: 1749-1760.
125. Schmid, D. and Münz, C. 2007. Innate and adaptive immunity through autophagy. Immunity 27: 11-21.
126. Schmid, D., Pypaert, M., and Münz, C. 2007. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26: 79-92.
127. Schworer, C.M., Shiffer, K.A., and Mortimore, G.E. 1981. Quantitative relationship between autophagy and proteolysis during graded amino acid deprivation in perfused rat liver. J. Biol. Chem. 256: 7652-7658.
128. Scott, R.C., Schuldiner, O., and Neufeld, T.P. 2004. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7: 167-178.
129. Shintani, T. and Klionsky, D.J. 2004. Autophagy in health and disease: A double-edged sword. Science 306: 990-995.
130. Singh, S.B., Davis, A.S., Taylor, G.A., and Deretic, V. 2006. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313: 1438-1441.
131. Suriapranata, I., Epple, U.D., Bernreuther, D., Bredschneider, M., Sovarasteanu, K., and Thumm, M. 2000. The breakdown of autophagic vesicles inside the vacuole depends on Aut4p. J. Cell Sci. 113: 4025-4033.
132. Suzuki, K. and Ohsumi, Y. 2007. Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. FEBS Lett. 581: 2156-2161.
133. Suzuki, K., Kirisako, T., Kamada, Y., Mizushima, N., Noda, T., and Ohsumi, Y. 2001. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 20: 5971-5981.
134. Suzuki, K., Kubota, Y., Sekito, T., and Ohsumi, Y. 2007. Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 12: 209-218.
135. Swanson, M.S. and Fernandez-Moreira, E. 2002. A microbial strategy to multiply in macrophages: The pregnant pause. Traffic 3: 170-177.
136. Takacs-Vellai, K., Vellai, T., Puoti, A., Passannante, M., Wicky, C., Streit, A., Kovacs, A.L., and Muller, F. 2005. Inactivation of the autophagy gene bec-1 triggers apoptotic cell death in C. elegans. Curr. Biol. 15: 1513-1517.
137. Takeshige, K., Baba, M., Tsuboi, S., Noda, T., and Ohsumi, Y. 1992. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J. Cell Biol. 119: 301-311.
138. Tallóczy, Z., Jiang, W., Virgin, H.W.T., Leib, D.A., Scheuner, D., Kaufman, R.J., Eskelinen, E.-L., and Levine, B. 2002. Regulation of starvation- and virus-induced autophagy by the eIF2α kinase signaling pathway. Proc. Natl. Acad. Sci. 99: 190-195.
139. Tanida, I., Minematsu-Ikeguchi, N., Ueno, T., and Kominami, E. 2005. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 1: 84-91.
140. Teter, S.A., Eggerton, K.P., Scott, S.V., Kim, J., Fischer, A.M., and Klionsky, D.J. 2001. Degradation of lipid vesicles in the yeast vacuole requires function of Cvt17, a putative lipase. J. Biol. Chem. 276: 2083-2087.
141. Thorburn, J., Moore, F., Rao, A., Barclay, W.W., Thomas, L.R., Grant, K.W., Cramer, S.D., and Thorburn, A. 2005. Selective inactivation of a Fas-associated death domain protein (FADD)-dependent apoptosis and autophagy pathway in immortal epithelial cells. Mol. Biol. Cell 16: 1189-1199.
142. Tooze, J., Hollinshead, M., Ludwig, T., Howell, K., Hoflack, B., and Kern, H. 1990. In exocrine pancreas, the basolateral endocytic pathway converges with the autophagic pathway immediately after the early endosome. J. Cell Biol. 111: 329-345.
143. Tsukada, M. and Ohsumi, Y. 1993. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333: 169-174.
144. Vabulas, R.M. and Hartl, F.U. 2005. Protein synthesis upon acute nutrient restriction relies on proteasome function. Science 310: 1960-1963.
145. Wang, Q.J., Ding, Y., Kohtz, S., Mizushima, N., Cristea, I.M., Rout, M.P., Chait, B.T., Zhong, Y., Heintz, N., and Yue, Z. 2006. Induction of autophagy in axonal dystrophy and degeneration. J. Neurosci. 26: 8057-8068.
146. Wooten, M.W., Hu, X., Babu, J.R., Seibenhener, M.L., Geetha, T., Paine, M.G., and Wooten, M.C. 2006. Signaling, polyubiquitination, trafficking, and inclusions: Sequestosome 1/p62's role in neurodegenerative disease. J. Biomed. Biotechnol. 2006: 62079. doi: 10.1155/JBB/2006/62079.
147. Xiong, Y., Contento, A.L., and Bassham, D.C. 2007a. Disruption of autophagy results in constitutive oxidative stress in Arabidopsis. Autophagy 3: 257-258.
148. Xiong, Y., Contento, A.L., Nguyen, P.Q., and Bassham, D.C. 2007b. Degradation of oxidized proteins by autophagy during oxidative stress in Arabidopsis. Plant Physiol. 143: 291-299.
149. Yan, L., Vatner, D.E., Kim, S.J., Ge, H., Masurekar, M., Massover, W.H., Yang, G., Matsui, Y., Sadoshima, J., and Vatner, S.F. 2005. Autophagy in chronically ischemic myocardium. Proc. Natl. Acad. Sci. 102: 13807-13812.
150. Yang, Z., Huang, J., Geng, J., Nair, U., and Klionsky, D.J. 2006. Atg22 recycles amino acids to link the degradative and recycling functions of autophagy. Mol. Biol. Cell 17: 5094-5104.
151. Yorimitsu, T., Nair, U., Yang, Z., and Klionsky, D.J. 2006. Endoplasmic reticulum stress triggers autophagy. J. Biol. Chem. 281: 30299-30304.
152. Yoshimoto, K., Hanaoka, H., Sato, S., Kato, T., Tabata, S., Noda, T., and Ohsumi, Y. 2004. Processing of ATG8s, ubiquitin-like proteins, and their deconjugation by ATG4s are essential for plant autophagy. Plant Cell 16: 2967-2983.
153. 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 β-amyloid peptide-generating pathway activated in Alzheimer's disease. J. Cell Biol. 171: 87-98.
154. Yu, L., Wan, F., Dutta, S., Welsh, S., Liu, Z., Freundt, E., Baehrecke, E.H., and Lenardo, M. 2006. Autophagic programmed cell death by selective catalase degradation. Proc. Natl. Acad. Sci. 103: 4952-4957.
155. Yue, Z., Jin, S., Yang, C., Levine, A.J., and Heintz, N. 2003. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl. Acad. Sci. 100: 15077-15082.
156. Zeng, X., Overmeyer, J.H., and Maltese, W.A. 2006. Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. J. Cell Sci. 119: 259-270.
157. Zhang, H., Monken, C.E., Zhang, Y., Lenard, J., Mizushima, N., Lattime, E.C., and Jin, S. 2006. Cellular autophagy machinery is not required for vaccinia virus replication and maturation. Autophagy 2: 91-95.
158. Zhang, Y., Qi, H., Taylor, R., Xu, W., Liu, L.F., and Jin, S. 2007. The role of autophagy in mitochondria maintenance: Characterization of mitochondrial functions in autophagy-deficient S. cerevisiae strains. Autophagy 3: 337-346.
159. Zhao, Z., Thackray, L.B., Miller, B.C., Lynn, T.M., Becker, M.M., Ward, E., Mizushima, N., Denison, M.R., and Virgin, H.W.T. 2007. Coronavirus replication does not require the autophagy gene ATG5. Autophagy 3: 581-585.