Mammalian Autophagy: How Does It Work?

Annual Review of Biochemistry

Volumn 85, Issue , 2016, Pages 685-713

  Bento, Carla F ^a   Renna, Maurizio ^a   Ghislat, Ghita ^a   Puri, Claudia ^a   Ashkenazi, Avraham ^a   Vicinanza, Mariella ^a   Menzies, Fiona M ^a   Rubinsztein, David C ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

Autophagosome biogenesis; Autophagy; Endocytosis; Lysosome; Membrane trafficking; Structural biology

Indexed keywords

CARGO RECEPTOR; MEMBRANE TETHERING FACTOR; PHOSPHATIDYLINOSITOL 3 KINASE; RAB PROTEIN; RECEPTOR; REGULATOR PROTEIN; SNARE PROTEIN; UBIQUITIN; UNCLASSIFIED DRUG; WIPI PROTEIN; AUTOPHAGY RELATED PROTEIN;

ARTICLE; AUTOPHAGOSOME; AUTOPHAGY; CELL FUSION; CELL MIGRATION; CONJUGATION; HUMAN; MAMMAL; MOLECULAR BIOLOGY; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN PROCESSING; PROTEIN STRUCTURE; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; ANIMAL; CHEMISTRY; CYTOSKELETON; ENDOCYTOSIS; GENETICS; LYSOSOME; METABOLISM; MOLECULAR MODEL; PHAGOSOME; SACCHAROMYCES CEREVISIAE;

ANIMALS; AUTOPHAGY; AUTOPHAGY-RELATED PROTEINS; CLASS III PHOSPHATIDYLINOSITOL 3-KINASES; CYTOSKELETON; ENDOCYTOSIS; HUMANS; LYSOSOMES; MAMMALS; MODELS, MOLECULAR; PHAGOSOMES; PROTEIN PROCESSING, POST-TRANSLATIONAL; RAB GTP-BINDING PROTEINS; SACCHAROMYCES CEREVISIAE; SIGNAL TRANSDUCTION; SNARE PROTEINS;

EID: 84973633815     PISSN: 00664154     EISSN: 15454509     Source Type: Book Series    
DOI: 10.1146/annurev-biochem-060815-014556     Document Type: Article

References (174)

1. Rubinsztein DC, Bento CF, Deretic V. 2015. Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. J. Exp. Med. 212:979-90
2. Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH, et al. 2015. Autophagy in malignant transformation and cancer progression. EMBO J. 34:856-80
3. Rubinsztein DC, Codogno P, Levine B. 2012. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11:709-30
4. Ohsumi Y. 2014. Historical landmarks of autophagy research. Cell Res. 24:9-23
5. McAlpine F, Williamson LE, Tooze SA, Chan EY. 2013. Regulation of nutrient-sensitive autophagy by uncoordinated 51-like kinases 1 and 2. Autophagy 9:361-73
6. Itakura E, Mizushima N. 2010. Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 6:764-76
7. Seglen PO, Gordon PB. 1982. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. PNAS 79:1889-92
8. Ronan B, Flamand O, Vescovi L, Dureuil C, Durand L, et al. 2014. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat. Chem. Biol. 10:1013-19
9. DowdleWE, Nyfeler B, Nagel J, EllingRA, Liu S, et al. 2014. SelectiveVPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat. Cell Biol. 16:1069-79
10. Dooley HC, Razi M, Polson HE, Girardin SE, Wilson MI, Tooze SA. 2014. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol. Cell 55:238-52
11. Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, et al. 1998. A protein conjugation system essential for autophagy. Nature 395:395-98
12. Sakoh-Nakatogawa M, Matoba K, Asai E, KirisakoH, Ishii J, et al. 2013. Atg12-Atg5 conjugate enhances E2 activity of Atg3 by rearranging its catalytic site. Nat. Struct. Mol. Biol. 20:433-39
13. Kirisako T, BabaM, Ishihara N, Miyazawa K, OhsumiM, et al. 1999. Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J. Cell Biol. 147:435-46
14. Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V, Elazar Z. 2010. LC3 and GATE-16/ GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis. EMBO J. 29:1792-802
15. Orsi A, Razi M, Dooley HC, Robinson D, Weston AE, et al. 2012. Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol. Biol. Cell 23:1860-73
16. Young AR, Chan EY, Hu XW, Kochl R, Crawshaw SG, et al. 2006. Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J. Cell Sci. 119:3888-900
17. Puri C, Renna M, Bento CF, Moreau K, Rubinsztein DC. 2013. Diverse autophagosome membrane sources coalesce in recycling endosomes. Cell 154:1285-99
18. Popovic D, Dikic I. 2014. TBC1D5 and the AP2 complex regulate ATG9 trafficking and initiation of autophagy. EMBO Rep. 15:392-401
19. Moreau K, Fleming A, Imarisio S, Lopez Ramirez A, Mercer JL, et al. 2014. PICALM modulates autophagy activity and tau accumulation. Nat. Commun. 5:4998
20. Moreau K, RavikumarB, RennaM, Puri C, RubinszteinDC. 2011. Autophagosome precursor maturation requires homotypic fusion. Cell 146:303-17
21. Pfisterer SG, BakulaD, Frickey T, Cezanne A, BriggerD, et al. 2014. Lipid droplet and early autophagosomal membrane targeting of Atg2A and Atg14L in human tumor cells. J. Lipid Res. 55:1267-78
22. Velikkakath AK, Nishimura T, Oita E, Ishihara N, Mizushima N. 2012. Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets. Mol. Biol. Cell 23:896-909
23. Kim J, Kundu M, Viollet B, Guan KL. 2011. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13:132-41
24. Egan D, Kim J, Shaw RJ, Guan KL. 2011. The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 7:643-44
25. Bach M, Larance M, James DE, Ramm G. 2011. The serine/threonine kinase ULK1 is a target of multiple phosphorylation events. Biochem. J. 440:283-91
26. Peña-Llopis S, Vega-Rubin-de-Celis S, Schwartz JC, Wolff NC, Tran TA, et al. 2011. Regulation of TFEB and V-ATPases by mTORC1. EMBO J. 30:3242-58
27. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, et al. 2011. TFEB links autophagy to lysosomal biogenesis. Science 332:1429-33
28. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, et al. 2012. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31:1095-108
29. Renna M, Bento CF, Fleming A, Menzies FM, Siddiqi FH, et al. 2013. IGF-1 receptor antagonism inhibits autophagy. Hum. Mol. Genet. 22:4528-44
30. Zavodszky E, Seaman MN, Moreau K, Jimenez-Sanchez M, Breusegem SY, et al. 2014. Mutation in VPS35 associated with Parkinson's disease impairsWASH complex association and inhibits autophagy. Nat. Commun. 5:3828
31. Moreau K, Ghislat G, Hochfeld W, Renna M, Zavodszky E, et al. 2015. Transcriptional regulation of Annexin A2 promotes starvation-induced autophagy. Nat. Commun. 6:8045
32. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, et al. 2009. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat. Cell Biol. 11:468-76
33. Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, et al. 2007. Ambra1 regulates autophagy and development of the nervous system. Nature 447:1121-25
34. Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, et al. 2007. Functional and physical interaction between Bcl-XL and a BH3-like domain in Beclin-1. EMBO J. 26:2527-39
35. Luo S, Garcia-Arencibia M, Zhao R, Puri C, Toh PP, et al. 2012. Bim inhibits autophagy by recruiting Beclin 1 to microtubules. Mol. Cell 47:359-70
36. Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. 2008. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol. Cell 30:678-88
37. Russell RC, Tian Y, Yuan H, Park HW, Chang YY, et al. 2013. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol. 15:741-50
38. Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G, et al. 2010. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J. Cell Biol. 191:155-68
39. Shi CS, Kehrl JH. 2010. TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control TLR4-induced autophagy. Sci. Signal. 3:ra42
40. Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V, et al. 2013. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat. Cell Biol. 15:406-16
41. Xia P, Wang S, Du Y, Zhao Z, Shi L, et al. 2013. WASH inhibits autophagy through suppression of Beclin 1 ubiquitination. EMBO J. 32:2685-96
42. Liu J, Xia H, Kim M, Xu L, Li Y, et al. 2011. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 147:223-34
43. Platta HW, Abrahamsen H, Thoresen SB, Stenmark H. 2012. Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1. Biochem. J. 441:399-406
44. SunT, Li X, Zhang P, Chen WD, Zhang HL, et al. 2015. Acetylation of Beclin 1 inhibits autophagosome maturation and promotes tumour growth. Nat. Commun. 6:7215
45. Yang Y, Fiskus W, Yong B, Atadja P, Takahashi Y, et al. 2013. Acetylated hsp70 and KAP1-mediated Vps34 SUMOylation is required for autophagosome creation in autophagy. PNAS 110:6841-46
46. Xu D, Zhang T, Xiao J, Zhu K, Wei R, et al. 2015. Modification of BECN1 by ISG15 plays a crucial role in autophagy regulation by type I IFN/interferon. Autophagy 11:617-28
47. Codogno P, Mehrpour M, Proikas-Cezanne T. 2012. Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat. Rev. Mol. Cell Biol. 13:7-12
48. Zhou X, Wang L, Hasegawa H, Amin P, Han BX, et al. 2010. Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway. PNAS 107:9424-29
49. Mauthe M, JacobA, Freiberger S, Hentschel K, Stierhof YD, et al. 2011. Resveratrol-mediated autophagy requiresWIPI-1-regulated LC3 lipidation in the absence of induced phagophore formation. Autophagy 7:1448-61
50. Vicinanza M, Korolchuk VI, Ashkenazi A, Puri C, Menzies FM, et al. 2015. PI(5)P regulates autophagosome biogenesis. Mol. Cell 57:219-34
51. Devereaux K, Dall'armi C, Alcazar-Roman A, Ogasawara Y, Zhou X, et al. 2013. Regulation of mammalian autophagy by class II and III PI 3-kinases through PI3P synthesis. PLOS ONE 8:e76405
52. Behrends C, Sowa ME, Gygi SP, Harper JW. 2010. Network organization of the human autophagy system. Nature 466:68-76
53. Viaud J, Boal F, Tronchere H, Gaits-Iacovoni F, Payrastre B. 2014. Phosphatidylinositol 5-phosphate: A nuclear stress lipid and a tuner of membranes and cytoskeleton dynamics. BioEssays 36:260-72
54. Juhasz G, Neufeld TP. 2006. Autophagy: A forty-year search for a missing membrane source. PLOS Biol. 4:e36
55. Biazik J, Yla-Anttila P, Vihinen H, Jokitalo E, Eskelinen EL. 2015. Ultrastructural relationship of the phagophore with surrounding organelles. Autophagy 11:439-51
56. Hwang KM, Yang LC, Carrico CK, Schulz RA, Schenkman JB, Sartorelli AC. 1974. Production of membrane whorls in rat liver by some inhibitors of protein synthesis. J. Cell Biol. 62:20-31
57. Ishikawa T, Furuno K, Kato K. 1983. Ultrastructural studies on autolysosomes in rat hepatocytes after leupeptin treatment. Exp. Cell Res. 144:15-24
58. Locke M, Sykes AK. 1975. The role of the Golgi complex in the isolation and digestion of organelles. Tissue Cell 7:143-58
59. Yamamoto A, Masaki R, Tashiro Y. 1990. Characterization of the isolation membranes and the limiting membranes of autophagosomes in rat hepatocytes by lectin cytochemistry. J. Histochem. Cytochem. 38:573-80
60. Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A. 2009. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 11:1433-37
61. Axe EL, Walker SA, ManifavaM, Chandra P, Roderick HL, et al. 2008. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182:685-701
62. Kishi-Itakura C, Koyama-Honda I, Itakura E, MizushimaN. 2014. Ultrastructural analysis of autophagosome organization using mammalian autophagy-deficient cells. J. Cell Sci. 127:4089-102
63. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, et al. 2010. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141:656-67
64. Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, et al. 2013. Autophagosomes form at ERmitochondria contact sites. Nature 495:389-93
65. Maxfield FR, McGraw TE. 2004. Endocytic recycling. Nat. Rev. Mol. Cell Biol. 5:121-32
66. Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. 2010. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat. Cell Biol. 12:747-57
67. Bejarano E, Yuste A, Patel B, Stout RF Jr, Spray DC, Cuervo AM. 2014. Connexinsmodulate autophagosome biogenesis. Nat. Cell Biol. 16:401-14
68. Moreau K, Ravikumar B, Puri C, Rubinsztein DC. 2012. Arf6 promotes autophagosome formation via effects on phosphatidylinositol 4, 5-bisphosphate and phospholipase D. J. Cell Biol. 196:483-96
69. Jaber N, Dou Z, Chen JS, Catanzaro J, Jiang YP, et al. 2012. Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. PNAS 109:2003-8
70. Zeng X, Overmeyer JH, Maltese WA. 2006. Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. J. Cell Sci. 119:259-70
71. Ravikumar B, Imarisio S, Sarkar S, O'Kane CJ, Rubinsztein DC. 2008. Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. J. Cell Sci. 121:1649-60
72. Dou Z, Pan JA, Dbouk HA, Ballou LM, DeLeon JL, et al. 2013. Class IA PI3K p110?subunit promotes autophagy through Rab5 small GTPase in response to growth factor limitation. Mol. Cell 50:29-42
73. Longatti A, Lamb CA, Razi M, Yoshimura S, Barr FA, Tooze SA. 2012. TBC1D14 regulates autophagosome formation via Rab11-and ULK1-positive recycling endosomes. J. Cell Biol. 197:659-75
74. Knaevelsrud H, Carlsson SR, Simonsen A. 2013. SNX18 tubulates recycling endosomes for autophagosome biogenesis. Autophagy 9:1639-41
75. Ge L, Melville D, Zhang M, Schekman R. 2013. The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. ELife 2:e00947
76. Ge L, Zhang M, Schekman R. 2014. Phosphatidylinositol 3-kinase and COPII generate LC3 lipidation vesicles from the ER-Golgi intermediate compartment. ELife 3:e04135
77. Tan D, Cai Y, Wang J, Zhang J, Menon S, et al. 2013. The EM structure of the TRAPPIII complex leads to the identification of a requirement for COPII vesicles on the macroautophagy pathway. PNAS 110:19432-37
78. Stolz A, Ernst A, Dikic I. 2014. Cargo recognition and trafficking in selective autophagy. Nat. Cell Biol. 16:495-501
79. Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, et al. 2015. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309-14
80. Nair U, YenWL, Mari M, Cao Y, Xie Z, et al. 2012. A role for Atg8-PE deconjugation in autophagosome biogenesis. Autophagy 8:780-93
81. Yu ZQ, Ni T, Hong B, Wang HY, Jiang FJ, et al. 2012. Dual roles of Atg8-PE deconjugation by Atg4 in autophagy. Autophagy 8:883-92
82. Monastyrska I, Rieter E, Klionsky DJ, Reggiori F. 2009. Multiple roles of the cytoskeleton in autophagy. Biol. Rev. Camb. Philos. Soc. 84:431-48
83. Hunt SD, Stephens DJ. 2011. The role of motor proteins in endosomal sorting. Biochem. Soc. Trans. 39:1179-84
84. Fass E, ShvetsE, Degani I, HirschbergK, Elazar Z. 2006. Microtubules support production of starvationinduced autophagosomes but not their targeting and fusion with lysosomes. J. Biol. Chem. 281:36303-16
85. Jahreiss L, Menzies FM, Rubinsztein DC. 2008. The itinerary of autophagosomes: from peripheral formation to kiss-and-run fusion with lysosomes. Traffic 9:574-87
86. Maday S, Wallace KE, Holzbaur EL. 2012. Autophagosomes initiate distally andmature during transport toward the cell soma in primary neurons. J. Cell Biol. 196:407-17
87. Cheng XT, Zhou B, Lin MY, Cai Q, Sheng ZH. 2015. Axonal autophagosomes recruit dynein for retrograde transport through fusion with late endosomes. J. Cell Biol. 209:377-86
88. Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C, et al. 2005. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat. Genet. 37:771-76
89. Cardoso CM, Groth-Pedersen L, Hoyer-Hansen M, Kirkegaard T, Corcelle E, et al. 2009. Depletion of kinesin 5B affects lysosomal distribution and stability and induces peri-nuclear accumulation of autophagosomes in cancer cells. PLOS ONE 4:e4424
90. Korolchuk VI, Saiki S, Lichtenberg M, Siddiqi FH, Roberts EA, et al. 2011. Lysosomal positioning coordinates cellular nutrient responses. Nat. Cell Biol. 13:453-60
91. Hartman MA, Finan D, Sivaramakrishnan S, Spudich JA. 2011. Principles of unconventional myosin function and targeting. Annu. Rev. Cell Dev. Biol. 27:133-55
92. Lee JY, Koga H, Kawaguchi Y, Tang W, Wong E, et al. 2010. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J. 29:969-80
93. Tumbarello DA, Waxse BJ, Arden SD, Bright NA, Kendrick-Jones J, Buss F. 2012. Autophagy receptors link myosin VI to autophagosomes to mediate Tom1-dependent autophagosome maturation and fusion with the lysosome. Nat. Cell Biol. 14:1024-35
94. Stenmark H. 2009. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 10:513-25
95. Jordens I, Fernandez-Borja M, MarsmanM, Dusseljee S, JanssenL, et al. 2001. TheRab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors. Curr. Biol. 11:1680-85
96. Pankiv S, Alemu EA, Brech A, Bruun JA, Lamark T, et al. 2010. FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport. J. Cell Biol. 188:253-69
97. Hyttinen JM, Niittykoski M, Salminen A, Kaarniranta K. 2013. Maturation of autophagosomes and endosomes: A key role for Rab7. Biochim. Biophys. Acta 1833:503-10
98. Huotari J, Helenius A. 2011. Endosome maturation. EMBO J. 30:3481-500
99. Ganley IG, Wong PM, Gammoh N, Jiang X. 2011. Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol. Cell 42:731-43
100. Mauvezin C, Nagy P, Juhasz G, Neufeld TP. 2015. Autophagosome-lysosome fusion is independent of V-ATPase-mediated acidification. Nat. Commun. 6:7007
101. Poteryaev D, Datta S, Ackema K, Zerial M, Spang A. 2010. Identification of the switch in early-to-late endosome transition. Cell 141:497-508
102. Liang C, Lee JS, Inn KS, Gack MU, Li Q, et al. 2008. Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat. Cell Biol. 10:776-87
103. Sun Q, Westphal W, Wong KN, Tan I, Zhong Q. 2010. Rubicon controls endosome maturation as a Rab7 effector. PNAS 107:19338-43
104. Tabata K, Matsunaga K, Sakane A, Sasaki T, Noda T, Yoshimori T. 2010. Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain. Mol. Biol. Cell 21:4162-72
105. Wang H, Sun HQ, Zhu X, Zhang L, Albanesi J, et al. 2015. GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion. PNAS 112:7015-20
106. Brocker C, Engelbrecht-Vandre S, Ungermann C. 2010. Multisubunit tethering complexes and their role in membrane fusion. Curr. Biol. 20:R943-52
107. McEwan DG, Popovic D, Gubas A, Terawaki S, Suzuki H, et al. 2015. PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. Mol. Cell 57:39-54
108. Wartosch L, Gunesdogan U, Graham SC, Paul Luzio J. 2015. Recruitment of VPS33A to HOPS by VPS16 is required for lysosome fusion with endosomes and autophagosomes. Traffic 16:727-42
109. Ogawa M, Yoshikawa Y, Kobayashi T, Mimuro H, Fukumatsu M, et al. 2011. A Tecpr1-dependent selective autophagy pathway targets bacterial pathogens. Cell Host Microbe 9:376-89
110. Chen D, Fan W, Lu Y, Ding X, Chen S, Zhong Q. 2012. A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate. Mol. Cell 45:629-41
111. Kim JH, Hong SB, Lee JK, Han S, Roh KH, et al. 2015. Insights into autophagosome maturation revealed by the structures of ATG5 with its interacting partners. Autophagy 11:75-87
112. Jahn R, Scheller RH. 2006. SNAREs-engines for membrane fusion. Nat. Rev. Mol. Cell Biol. 7:631-43
113. Pryor PR, Mullock BM, Bright NA, LindsayMR, Gray SR, et al. 2004. CombinatorialSNAREcomplexes with VAMP7 or VAMP8 define different late endocytic fusion events. EMBO Rep. 5:590-95
114. Furuta N, Fujita N, Noda T, Yoshimori T, Amano A. 2010. Combinational soluble N-ethylmaleimidesensitive factor attachment protein receptor proteins VAMP8 and Vti1b mediate fusion of antimicrobial and canonical autophagosomes with lysosomes. Mol. Biol. Cell 21:1001-10
115. Fraldi A, Annunziata F, Lombardi A, Kaiser HJ, Medina DL, et al. 2010. Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders. EMBO J. 29:3607-20
116. FaderCM, Sanchez DG, Mestre MB, ColomboMI. 2009. TI-VAMP/VAMP7 and VAMP3/cellubrevin: Two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochim. Biophys. Acta 1793:1901-16
117. Renna M, SchaffnerC, Winslow AR, Menzies FM, Peden AA, et al. 2011. Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex. J. Cell Sci. 124:469-82
118. Itakura E, Kishi-Itakura C, Mizushima N. 2012. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151:1256-69
119. Takats S, Nagy P, Varga A, Pircs K, Karpati M, et al. 2013. Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila. J. Cell Biol. 201:531-39
120. Diao J, Liu R, Rong Y, ZhaoM, Zhang J, et al. 2015. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature 520:563-66
121. Razi M, Chan EY, Tooze SA. 2009. Early endosomes and endosomal coatomer are required for autophagy. J. Cell Biol. 185:305-21
122. Rusten TE, Stenmark H. 2009. How do ESCRT proteins control autophagy? J. Cell Sci. 122:2179-83
123. Lazarus MB, Novotny CJ, Shokat KM. 2015. Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors. ACS Chem. Biol. 10:257-61
124. Fujioka Y, Suzuki SW, Yamamoto H, Kondo-Kakuta C, Kimura Y, et al. 2014. Structural basis of starvation-induced assembly of the autophagy initiation complex. Nat. Struct. Mol. Biol. 21:513-21
125. Ragusa MJ, Stanley RE, Hurley JH. 2012. Architecture of the Atg17 complex as a scaffold for autophagosome biogenesis. Cell 151:1501-12
126. Mao K, Chew LH, Inoue-Aono Y, Cheong H, Nair U, et al. 2013. Atg29 phosphorylation regulates coordination of the Atg17-Atg31-Atg29 complex with the Atg11 scaffold during autophagy initiation. PNAS 110:E2875-84
127. Kofinger J, Ragusa MJ, Lee IH, Hummer G, Hurley JH. 2015. Solution structure of the Atg1 complex: implications for the architecture of the phagophore assembly site. Structure 23:809-18
128. Stanley RE, Ragusa MJ, Hurley JH. 2014. The beginning of the end: how scaffolds nucleate autophagosome biogenesis. Trends Cell Biol. 24:73-81
129. Jao CC, Ragusa MJ, Stanley RE, Hurley JH. 2013. A HORMA domain in Atg13 mediates PI 3-kinase recruitment in autophagy. PNAS 110:5486-91
130. Suzuki H, Kaizuka T, Mizushima N, Noda NN. 2015. Structure of the Atg101-Atg13 complex reveals essential roles of Atg101 in autophagy initiation. Nat. Struct. Mol. Biol. 22:572-80
131. Suzuki SW, Yamamoto H, Oikawa Y, Kondo-Kakuta C, Kimura Y, et al. 2015. Atg13 HORMA domain recruits Atg9 vesicles during autophagosome formation. PNAS 112:3350-55
132. Miller S, Tavshanjian B, Oleksy A, Perisic O, Houseman BT, et al. 2010. Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327:1638-42
133. Hurley JH, Schulman BA. 2014. Atomistic autophagy: The structures of cellular self-digestion. Cell 157:300-11
134. Feng W, Huang S, Wu H, Zhang M. 2007. Molecular basis of Bcl-xL's target recognition versatility revealed by the structure of Bcl-xL in complex with the BH3 domain of Beclin-1. J. Mol. Biol. 372:223-35
135. Oberstein A, Jeffrey PD, Shi Y. 2007. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J. Biol. Chem. 282:13123-32
136. Li X, He L, Che KH, Funderburk SF, Pan L, et al. 2012. Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG. Nat. Commun. 3:662
137. Wei Y, Zou Z, Becker N, Anderson M, SumpterR, et al. 2013. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistancE. Cell 154:1269-84
138. HuangW, ChoiW, HuW, Mi N, Guo Q, et al. 2012. Crystal structure and biochemical analyses reveal Beclin 1 as a novel membrane binding protein. Cell Res. 22:473-89
139. Noda NN, Kobayashi T, Adachi W, Fujioka Y, Ohsumi Y, Inagaki F. 2012. Structure of the novel C-terminal domain of vacuolar protein sorting 30/autophagy-related protein 6 and its specific role in autophagy. J. Biol. Chem. 287:16256-66
140. Baskaran S, Carlson LA, Stjepanovic G, Young LN, Kim do J, et al. 2014. Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex. ELife 3:e05115
141. Rostislavleva K, Soler N, Ohashi Y, Zhang L, Pardon E, et al. 2015. Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes. Science 350:aac7365
142. Baskaran S, Ragusa MJ, Boura E, Hurley JH. 2012. Two-site recognition of phosphatidylinositol 3-phosphate by PROPPINs in autophagy. Mol. Cell 47:339-48
143. Krick R, Busse RA, Scacioc A, Stephan M, Janshoff A, et al. 2012. Structural and functional characterization of the two phosphoinositide binding sites of PROPPINs, a propeller protein family. PNAS 109:E2042-49
144. Watanabe Y, Kobayashi T, Yamamoto H, Hoshida H, Akada R, et al. 2012. Structure-based analyses reveal distinct binding sites for Atg2 and phosphoinositides in Atg18. J. Biol. Chem. 287:31681-90
145. Noda NN, Inagaki F. 2015. Mechanisms of autophagy. Annu. Rev. Biophys. 44:101-22
146. Kaiser SE, Mao K, Taherbhoy AM, Yu S, Olszewski JL, et al. 2012. Noncanonical E2 recruitment by the autophagy E1 revealed by Atg7-Atg3 and Atg7-Atg10 structures. Nat. Struct. Mol. Biol. 19:1242-49
147. Yamaguchi M, Matoba K, Sawada R, Fujioka Y, Nakatogawa H, et al. 2012. Noncanonical recognition and UBL loading of distinct E2s by autophagy-essential Atg7. Nat. Struct. Mol. Biol. 19:1250-56
148. Yamaguchi M, Noda NN, Yamamoto H, Shima T, Kumeta H, et al. 2012. Structural insights into Atg10-mediated formation of the autophagy-essential Atg12-Atg5 conjugate. Structure 20:1244-54
149. Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, et al. 2007. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J. Biol. Chem. 282:37298-302
150. Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T. 2008. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol. Biol. Cell 19:2092-100
151. Matsushita M, Suzuki NN, Obara K, Fujioka Y, Ohsumi Y, Inagaki F. 2007. Structure of Atg5Atg16, a complex essential for autophagy. J. Biol. Chem. 282:6763-72
152. Fujioka Y, Noda NN, Nakatogawa H, Ohsumi Y, Inagaki F. 2010. Dimeric coiled-coil structure of Saccharomyces cerevisiae Atg16 and its functional significance in autophagy. J. Biol. Chem. 285:1508-15
153. Noda NN, Fujioka Y, Hanada T, Ohsumi Y, Inagaki F. 2013. Structure of the Atg12-Atg5 conjugate reveals a platform for stimulating Atg8-PE conjugation. EMBO Rep. 14:206-11
154. Otomo C, Metlagel Z, Takaesu G, Otomo T. 2013. Structure of the human ATG12?ATG5 conjugate required for LC3 lipidation in autophagy. Nat. Struct. Mol. Biol. 20:59-66
155. Hain AU, Weltzer RR, Hammond H, Jayabalasingham B, Dinglasan RR, et al. 2012. Structural characterization and inhibition of the Plasmodium Atg8-Atg3 interaction. J. Struct. Biol. 180:551-62
156. Hu C, Zhang X, Teng YB, Hu HX, LiWF. 2010. Structure of autophagy-related protein Atg8 from the silkworm Bombyx mori. Acta Crystallogr. Sect. F 66:787-90
157. Koopmann R, Muhammad K, Perbandt M, Betzel C, Duszenko M. 2009. Trypanosoma brucei ATG8: structural insights into autophagic-like mechanisms in protozoa. Autophagy 5:1085-91
158. Nakatogawa H, Ichimura Y, Ohsumi Y. 2007. Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130:165-78
159. Noda NN, Kumeta H, Nakatogawa H, Satoo K, Adachi W, et al. 2008. Structural basis of target recognition by Atg8/LC3 during selective autophagy. Genes Cells 13:1211-18
160. Sugawara K, Suzuki NN, Fujioka Y, Mizushima N, Ohsumi Y, Inagaki F. 2004. The crystal structure of microtubule-associated protein light chain 3, a mammalian homologue of Saccharomyces cerevisiae Atg8. Genes Cells 9:611-18
161. Weidberg H, Shpilka T, Shvets E, Abada A, Shimron F, Elazar Z. 2011. LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. Dev. Cell 20:444-54
162. Kumeta H, Watanabe M, Nakatogawa H, Yamaguchi M, Ogura K, et al. 2010. The NMR structure of the autophagy-related protein Atg8. J. Biomol. NMR 47:237-41
163. Ichimura Y, Kumanomidou T, Sou YS, Mizushima T, Ezaki J, et al. 2008. Structural basis for sorting mechanism of p62 in selective autophagy. J. Biol. Chem. 283:22847-57
164. Birgisdottir AB, Lamark T, Johansen T. 2013. The LIR motif-crucial for selective autophagy. J. Cell Sci. 126:3237-47
165. Kumanomidou T, Mizushima T, Komatsu M, Suzuki A, Tanida I, et al. 2006. The crystal structure of human Atg4b, a processing and de-conjugating enzyme for autophagosome-forming modifiers. J. Mol. Biol. 355:612-18
166. Satoo K, Noda NN, Kumeta H, Fujioka Y, Mizushima N, et al. 2009. The structure of Atg4B-LC3 complex reveals themechanism ofLC3processing and delipidation during autophagy. EMBOJ. 28:1341-50
167. Sugawara K, Suzuki NN, Fujioka Y, Mizushima N, Ohsumi Y, Inagaki F. 2005. Structural basis for the specificity and catalysis of human Atg4B responsible for mammalian autophagy. J. Biol. Chem. 280:40058-65
168. Hong SB, Kim BW, Lee KE, Kim SW, Jeon H, et al. 2011. Insights into noncanonical E1 enzyme activation from the structure of autophagic E1 Atg7 with Atg8. Nat. Struct. Mol. Biol. 18:1323-30
169. Noda NN, Satoo K, Fujioka Y, Kumeta H, Ogura K, et al. 2011. Structural basis of Atg8 activation by a homodimeric E1, Atg7. Mol. Cell 44:462-75
170. Taherbhoy AM, Tait SW, Kaiser SE, Williams AH, Deng A, et al. 2011. Atg8 transfer from Atg7 to Atg3: A distinctive E1-E2 architecture and mechanism in the autophagy pathway. Mol. Cell 44:451-61
171. Yamada Y, Suzuki NN, Hanada T, Ichimura Y, Kumeta H, et al. 2007. The crystal structure of Atg3, an autophagy-related ubiquitin carrier protein (E2) enzyme that mediates Atg8 lipidation. J. Biol. Chem. 282:8036-43
172. Yamaguchi M, Noda NN, Nakatogawa H, Kumeta H, Ohsumi Y, Inagaki F. 2010. Autophagy-related protein 8 (Atg8) family interacting motif in Atg3 mediates the Atg3-Atg8 interaction and is crucial for the cytoplasm-to-vacuole targeting pathway. J. Biol. Chem. 285:29599-607
173. Nath S, Dancourt J, Shteyn V, Puente G, Fong WM, et al. 2014. Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3. Nat. Cell Biol. 16:415-24
174. Suzuki K, Kirisako T, Kamada Y, Mizushima N, Noda T, Ohsumi Y. 2001. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 20:5971-81