1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Biochemistry
  4. Volume 86, 2017
  5. Article

Annual Review of Biochemistry

Volume 86, 2017

Mechanisms of Autophagy Initiation

Abstract

Autophagy is the process of cellular self-eating by a double-membrane organelle, the autophagosome. A range of signaling processes converge on two protein complexes to initiate autophagy: the ULK1 (unc51-like autophagy activating kinase 1) protein kinase complex and the PI3KC3–C1 (class III phosphatidylinositol 3-kinase complex I) lipid kinase complex. Some 90% of the mass of these large protein complexes consists of noncatalytic domains and subunits, and the ULK1 complex has essential noncatalytic activities. Structural studies of these complexes have shed increasing light on the regulation of their catalytic and noncatalytic activities in autophagy initiation. The autophagosome is thought to nucleate from vesicles containing the integral membrane protein Atg9 (autophagy-related 9), COPII (coat protein complex II) vesicles, and possibly other sources. In the wake of reconstitution and super-resolution imaging studies, we are beginning to understand how the ULK1 and PI3KC3–C1 complexes might coordinate the nucleation and fusion of Atg9 and COPII vesicles at the start of autophagosome biogenesis.

Keyword(s): Atg1, COPII, membrane fusion, membrane remodeling, nanoscale biology, phosphatidylinositol 3-kinase, tethering complex, ULK1, vesicle, Vps34
Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-061516-044820
2017-06-20
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/biochem/86/1/annurev-biochem-061516-044820.html?itemId=/content/journals/10.1146/annurev-biochem-061516-044820&mimeType=html&fmt=ahah

Literature Cited

  1. Wen X, Klionsky DJ. 1.  2016. An overview of macroautophagy in yeast. J. Mol. Biol. 428:1681–99 [Google Scholar]
  2. Bento CF, Renna M, Ghislat G, Puri C, Ashkenazi A. 2.  et al. 2016. Mammalian autophagy: How does it work?. Annu. Rev. Biochem. 85:685–713 [Google Scholar]
  3. Shaid S, Brandts CH, Serve H, Dikic I. 3.  2013. Ubiquitination and selective autophagy. Cell Death Differ 20:21–30 [Google Scholar]
  4. Zaffagnini G, Martens S. 4.  2016. Mechanisms of selective autophagy. J. Mol. Biol. 428:1714–24 [Google Scholar]
  5. Menzies FM, Fleming A, Rubinsztein DC. 5.  2015. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci. 16:345–57 [Google Scholar]
  6. Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH. 6.  et al. 2015. Autophagy in malignant transformation and cancer progression. EMBO J 34:856–80 [Google Scholar]
  7. Mizushima N, Komatsu M. 7.  2011. Autophagy: renovation of cells and tissues. Cell 147:728–41 [Google Scholar]
  8. Gomes LC, Dikic I. 8.  2014. Autophagy in antimicrobial immunity. Mol. Cell 54:224–33 [Google Scholar]
  9. Suzuki K, Kirisako T, Kamada Y, Mizushima N, Noda T, Ohsumi Y. 9.  2001. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J 20:5971–81 [Google Scholar]
  10. Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL. 10.  et al. 2008. Autophagosome formation from compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182:685–701 [Google Scholar]
  11. Lamb CA, Yoshimori T, Tooze SA. 11.  2013. The autophagosome: origins unknown, biogenesis complex. Nat. Rev. Mol. Cell Biol. 14:759–74 [Google Scholar]
  12. Sawa-Makarska J, Abert C, Romanov J, Zens B, Ibiricu I, Martens S. 12.  2014. Cargo binding to Atg19 unmasks additional Atg8 binding sites to mediate membrane-cargo apposition during selective autophagy. Nat. Cell Biol. 16:425–33 [Google Scholar]
  13. Wurzer B, Zaffagnini G, Fracchiolla D, Turco E, Abert C. 13.  et al. 2015. Oligomerization of p62 allows for selection of ubiquitinated cargo and isolation membrane during selective autophagy. eLife 4:e08941 [Google Scholar]
  14. Mi N, Chen Y, Wang S, Chen MR, Zhao MK. 14.  et al. 2015. CapZ regulates autophagosomal membrane shaping by promoting actin assembly inside the isolation membrane. Nat. Cell Biol. 17:1112–23 [Google Scholar]
  15. Mizushima N, Yoshimori T, Ohsumi Y. 15.  2011. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27:107–32 [Google Scholar]
  16. Hurley JH, Schulman BA. 16.  2014. Atomistic autophagy: the structures of cellular self-digestion. Cell 157:300–11 [Google Scholar]
  17. Suzuki H, Osawa T, Fujioka Y, Noda NN. 17.  2016. Structural biology of the core autophagy machinery. Curr. Opin. Struct. Biol. 43:10–17 [Google Scholar]
  18. Joo JH, Wang B, Frankel E, Ge L, Xu L. 18.  et al. 2016. The noncanonical role of ULK/ATG1 in ER-to-Golgi trafficking is essential for cellular homeostasis. Mol. Cell 62:491–506 [Google Scholar]
  19. Nair U, Jotwani A, Geng JF, Gammoh N, Richerson D. 19.  et al. 2011. SNARE proteins are required for macroautophagy. Cell 146:290–302 [Google Scholar]
  20. Moreau K, Ravikumar B, Renna M, Puri C, Rubinsztein DC. 20.  2011. Autophagosome precursor maturation requires homotypic fusion. Cell 146:303–17 [Google Scholar]
  21. Moreau K, Renna M, Rubinsztein DC. 21.  2013. Connections between SNAREs and autophagy. Trends Biochem. Sci. 38:57–63 [Google Scholar]
  22. Mancias JC, Kimmelman AC. 22.  2016. Mechanisms of selective autophagy in normal physiology and cancer. J. Mol. Biol. 428:1659–80 [Google Scholar]
  23. Mizushima N. 23.  2010. The role of the Atg1/ULK1 complex in autophagy regulation. Curr. Opin. Cell Biol. 22:132–39 [Google Scholar]
  24. Lin MG, Hurley JH. 24.  2016. Structure and function of the ULK1 complex in autophagy. Curr. Opin. Cell Biol. 39:61–68 [Google Scholar]
  25. Papinski D, Kraft C. 25.  2016. Regulation of autophagy by signalling through the Atg1/ULK1 complex. J. Mol. Biol. 428:1725–41 [Google Scholar]
  26. Ganley IG, Lam DH, Wang J, Ding X, Chen S, Jiang X. 26.  2009. ULK1·ATG13·FIP200 complex mediates mTOR signaling and is essential for autophagy. J. Biol. Chem. 284:12297–305 [Google Scholar]
  27. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A. 27.  et al. 2009. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20:1981–91 [Google Scholar]
  28. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM. 28.  et al. 2009. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20:1992–2003 [Google Scholar]
  29. Hara T, Takamura A, Kishi C, Iemura SI, Natsume T. 29.  et al. 2008. FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J. Cell Biol. 181:497–510 [Google Scholar]
  30. Jao CC, Ragusa MJ, Stanley RE, Hurley JH. 30.  2013. A HORMA domain in Atg13 mediates PI 3-kinase recruitment in autophagy. PNAS 110:5486–91 [Google Scholar]
  31. Suzuki H, Kaizuka T, Mizushima N, Noda NN. 31.  2015. Structure of the Atg101–Atg13 complex reveals essential roles of Atg101 in autophagy initiation. Nat. Struct. Mol. Biol. 22:572–80 [Google Scholar]
  32. Michel M, Schwarten M, Decker C, Nagel-Steger L, Willbold D, Weiergraber OH. 32.  2015. The mammalian autophagy initiator complex contains 2 HORMA domain proteins. Autophagy 11:2300–8 [Google Scholar]
  33. Qi SQ, Kim DJ, Stjepanovic G, Hurley JH. 33.  2015. Structure of the human Atg13-Atg101 HORMA heterodimer: an interaction hub within the ULK1 complex. Structure 23:1848–57 [Google Scholar]
  34. Fujioka Y, Suzuki SW, Yamamoto H, Kondo-Kakuta C, Kimura Y. 34.  et al. 2014. Structural basis of starvation-induced assembly of the autophagy initiation complex. Nat. Struct. Mol. Biol. 21:513–21 [Google Scholar]
  35. Yorimitsu T, Klionsky DJ. 35.  2005. Atg11 links cargo to the vesicle-forming machinery in the cytoplasm to vacuole targeting pathway. Mol. Biol. Cell 16:1593–605 [Google Scholar]
  36. Cheong H, Yorimitsu T, Reggiori F, Legakis JE, Wang CW, Klionsky DJ. 36.  2005. Atg17 regulates the magnitude of the autophagic response. Mol. Biol. Cell 16:3438–53 [Google Scholar]
  37. Kabeya Y, Kamada Y, Baba M, Takikawa H, Sasaki M, Ohsumi Y. 37.  2005. Atg17 functions in cooperation with Atg1 and Atg13 in yeast autophagy. Mol. Biol. Cell 16:2544–53 [Google Scholar]
  38. Kabeya Y, Noda NN, Fujioka Y, Suzuki K, Inagaki F, Ohsumi Y. 38.  2009. Characterization of the Atg17–Atg29–Atg31 complex specifically required for starvation-induced autophagy in Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 389:612–15 [Google Scholar]
  39. Ragusa MJ, Stanley RE, Hurley JH. 39.  2012. Architecture of the Atg17 complex as a scaffold for autophagosome biogenesis. Cell 151:1501–12 [Google Scholar]
  40. Bach M, Larance M, James DE, Ramm G. 40.  2011. The serine/threonine kinase ULK1 is a target of multiple phosphorylation events. Biochem. J. 440:283–91 [Google Scholar]
  41. Lazarus MB, Novotny CJ, Shokat KM. 41.  2015. Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors. ACS Chem. Biol. 10:257–61 [Google Scholar]
  42. Yeh YY, Wrasman K, Herman PK. 42.  2010. Autophosphorylation within the Atg1 activation loop is required for both kinase activity and the induction of autophagy in Saccharomyces cerevisiae. Genetics 185:871–82 [Google Scholar]
  43. Kijanska M, Dohnal I, Reiter W, Kaspar S, Stoffel I. 43.  et al. 2010. Activation of Atg1 kinase in autophagy by regulated phosphorylation. Autophagy 6:1168–78 [Google Scholar]
  44. Kamber RA, Shoemaker CJ, Denic V. 44.  2015. Receptor-bound targets of selective autophagy use a scaffold protein to activate the Atg1 kinase. Mol. Cell 59:372–81 [Google Scholar]
  45. Yamamoto H, Fujioka Y, Suzuki SW, Noshiro D, Suzuki H. 45.  et al. 2016. The intrinsically disordered protein Atg13 mediates supramolecular assembly of autophagy initiation complexes. Dev. Cell 38:86–99 [Google Scholar]
  46. Liu CC, Lin YC, Chen YH, Chen CM, Pang LY. 46.  et al. 2016. Cul3-KLHL20 ubiquitin ligase governs the turnover of ULK1 and VPS34 complexes to control autophagy termination. Mol. Cell 61:84–97 [Google Scholar]
  47. Stjepanovic G, Davies CW, Stanley RE, Ragusa MJ, Kim DJ, Hurley JH. 47.  2014. Assembly and dynamics of the autophagy initiating Atg1 complex. PNAS 111:12793–98 [Google Scholar]
  48. Rao Y, Perna MG, Hofmann B, Beier V, Wollert T. 48.  2016. The Atg1–kinase complex tethers Atg9–vesicles to initiate autophagy. Nat. Commun. 7:10338 [Google Scholar]
  49. Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y. 49.  2000. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J. Cell Biol. 150:1507–13 [Google Scholar]
  50. Bar-Peled L, Sabatini DM. 50.  2014. Regulation of mTORC1 by amino acids. Trends Cell Biol 24:400–6 [Google Scholar]
  51. Kamada Y, Yoshino K, Kondo C, Kawamata T, Oshiro N. 51.  et al. 2010. Tor directly controls the Atg1 kinase complex to regulate autophagy. Mol. Cell. Biol. 30:1049–58 [Google Scholar]
  52. Kraft C, Kijanska M, Kalie E, Siergiejuk E, Lee SS. 52.  et al. 2012. Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy. EMBO J 31:3691–703 [Google Scholar]
  53. Hieke N, Loffler AS, Kaizuka T, Berleth N, Bohler P. 53.  et al. 2015. Expression of a ULK1/2 binding-deficient ATG13 variant can partially restore autophagic activity in ATG13-deficient cells. Autophagy 11:1471–83 [Google Scholar]
  54. Mihaylova MM, Shaw RJ. 54.  2011. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13:1016–23 [Google Scholar]
  55. Egan DF, Kim J, Shaw RJ, Guan KL. 55.  2011. The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 7:645–46 [Google Scholar]
  56. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA. 56.  et al. 2011. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–61 [Google Scholar]
  57. Kim J, Kundu M, Viollet B, Guan KL. 57.  2011. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13:132–41 [Google Scholar]
  58. Shang LB, Chen S, Du FH, Li S, Zhao LP, Wang XD. 58.  2011. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. PNAS 108:4788–93 [Google Scholar]
  59. Mack HID, Zheng B, Asara JM, Thomas SM. 59.  2012. AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization. Autophagy 8:1197–214 [Google Scholar]
  60. Rui Y-N, Xu Z, Patel B, Chen Z, Chen D. 60.  et al. 2015. Huntingtin functions as a scaffold for selective macroautophagy. Nat. Cell Biol. 17:262–75 [Google Scholar]
  61. Suzuki K, Kubota Y, Sekito T, Ohsumi Y. 61.  2007. Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 12:209–18 [Google Scholar]
  62. Chan EY, Longatti A, McKnight NC, Tooze SA. 62.  2009. Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol. Cell. Biol. 29:157–71 [Google Scholar]
  63. Alemu EA, Lamark T, Torgersen KM, Birgisdottir AB, Larsen KB. 63.  et al. 2012. ATG8 family proteins act as scaffolds for assembly of the ULK complex: sequence requirements for LC3-interacting region (LIR) motifs. J. Biol. Chem. 287:39275–90 [Google Scholar]
  64. Suzuki SW, Yamamoto H, Oikawa Y, Kondo-Kakuta C, Kimura Y. 64.  et al. 2015. Atg13 HORMA domain recruits Atg9 vesicles during autophagosome formation. PNAS 112:3350–55 [Google Scholar]
  65. Sekito T, Kawamata T, Ichikawa R, Suzuki K, Ohsumi Y. 65.  2009. Atg17 recruits Atg9 to organize the pre-autophagosomal structure. Genes Cells 14:525–38 [Google Scholar]
  66. Wang J, Menon S, Yamasaki A, Chou H-T, Walz T. 66.  et al. 2013. Ypt1 recruits the Atg1 kinase to the preautophagosomal structure. PNAS 110:9800–5 [Google Scholar]
  67. Kakuta S, Yamamoto H, Negishi L, Kondo-Kakuta C, Hayashi N, Ohsumi Y. 67.  2012. Atg9 vesicles recruit vesicle-tethering proteins Trs85 and Ypt1 to the autophagosome formation site. J. Biol. Chem. 287:44261–69 [Google Scholar]
  68. Behrends C, Sowa ME, Gygi SP, Harper JW. 68.  2010. Network organization of the human autophagy system. Nature 466:68–76 [Google Scholar]
  69. Lamb CA, Nuhlen S, Judith D, Frith D, Snijders AP. 69.  et al. 2016. TBC1D14 regulates autophagy via the TRAPP complex and ATG9 traffic. EMBO J 35:281–301 [Google Scholar]
  70. Webster CP, Smith EF, Bauer CS, Moller A, Hautbergue GM. 70.  et al. 2016. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J 35:1656–76 [Google Scholar]
  71. Papinski D, Schuschnig M, Reiter W, Wilhelm L, Barnes CA. 71.  et al. 2014. Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase. Mol. Cell 53:471–83 [Google Scholar]
  72. Egan DF, Chun MG, Vamos M, Zou H, Rong J. 72.  et al. 2015. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol. Cell 59:285–97 [Google Scholar]
  73. Russell RC, Tian Y, Yuan HX, Park HW, Chang YY. 73.  et al. 2013. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol. 15:741–50 [Google Scholar]
  74. Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G. 74.  et al. 2010. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J. Cell Biol. 191:155–68 [Google Scholar]
  75. Lim J, Lachenmayer ML, Wu S, Liu WC, Kundu M. 75.  et al. 2015. Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLOS Genet 11:e1004987 [Google Scholar]
  76. Wu WX, Tian WL, Hu Z, Chen G, Huang L. 76.  et al. 2014. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep 15:566–75 [Google Scholar]
  77. Abeliovich H, Zhang C, Dunn WA Jr., Shokat KM, Klionsky DJ. 77.  2003. Chemical genetic analysis of Apg1 reveals a non-kinase role in the induction of autophagy. Mol. Biol. Cell 14:477–90 [Google Scholar]
  78. Cheong H, Nair U, Geng JF, Klionsky DJ. 78.  2008. The Atg1 kinase complex is involved in the regulation of protein recruitment to initiate sequestering vesicle formation for nonspecific autophagy in Saccharomyces cerevisiae. Mol. Biol. Cell 19:668–81 [Google Scholar]
  79. Stanley RE, Ragusa MJ, Hurley JH. 79.  2014. The beginning of the end: how scaffolds nucleate autophagosome biogenesis. Trends Cell Biol 24:73–81 [Google Scholar]
  80. Köfinger J, Ragusa MJ, Lee IH, Hummer G, Hurley JH. 80.  2015. Solution structure of the Atg1 complex: implications for the architecture of the phagophore assembly site. Structure 23:809–18 [Google Scholar]
  81. Alers S, Loffler AS, Paasch F, Dieterle AM, Keppeler H. 81.  et al. 2011. Atg13 and FIP200 act independently of Ulk1 and Ulk2 in autophagy induction. Autophagy 7:1424–33 [Google Scholar]
  82. Backer JM. 82.  2016. The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34. Biochem. J. 473:2251–71 [Google Scholar]
  83. Kihara A, Noda T, Ishihara N, Ohsumi Y. 83.  2001. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J. Cell Biol. 152:519–30 [Google Scholar]
  84. Itakura E, Kishi C, Inoue K, Mizushima N. 84.  2008. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol. Biol. Cell 19:5360–72 [Google Scholar]
  85. Kametaka S, Okano T, Ohsumi M, Ohsumi Y. 85.  1998. Apg14p and Apg6/Vps30p form a protein complex essential for autophagy in the yeast, Saccharomyces cerevisiae. J. Biol. Chem. 273:22284–91 [Google Scholar]
  86. Obara K, Sekito T, Ohsumi Y. 86.  2006. Assortment of phosphatidylinositol 3-kinase complexes—Atg14p directs association of complex I to the pre-autophagosomal structure in Saccharomyces cerevisiae. Mol. Biol. Cell 17:1527–39 [Google Scholar]
  87. Sun Q, Fan W, Chen K, Ding X, Chen S, Zhong Q. 87.  2008. Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. PNAS 105:19211–16 [Google Scholar]
  88. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T. 88.  et al. 2009. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat. Cell Biol. 11:385–96 [Google Scholar]
  89. Zhong Y, Wang QJ, Li XT, Yan Y, Backer JM. 89.  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 [Google Scholar]
  90. Miller S, Tavshanjian B, Oleksy A, Perisic O, Houseman BT. 90.  et al. 2010. Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327:1638–42 [Google Scholar]
  91. Li XH, He LQ, Che KH, Funderburk SF, Pan LF. 91.  et al. 2012. Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG. Nat. Commun. 3:662 [Google Scholar]
  92. Noda NN, Kobayashi T, Adachi W, Fujioka Y, Ohsumi Y, Inagaki F. 92.  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 [Google Scholar]
  93. Huang W, Choi W, Hu W, Mi N, Guo Q. 93.  et al. 2012. Crystal structure and biochemical analyses reveal Beclin 1 as a novel membrane binding protein. Cell Res 22:473–89 [Google Scholar]
  94. Heenan EJ, Vanhooke JL, Temple BR, Betts L, Sondek JE, Dohlman HG. 94.  2009. Structure and function of Vps15 in the endosomal G protein signaling pathway. Biochemistry 48:6390–401 [Google Scholar]
  95. Baskaran S, Carlson LA, Stjepanovic G, Young LN, Kim DJ. 95.  et al. 2014. Architecture and dynamics of the autophagic phosphatidylinostol 3-kinase complex. eLife 3:e05115 [Google Scholar]
  96. Rostislavleva K, Soler N, Ohashi Y, Zhang LF, Pardon E. 96.  et al. 2015. Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes. Science 350:aac7365 [Google Scholar]
  97. Fan W, Nassiri A, Zhong Q. 97.  2011. Autophagosome targeting and membrane curvature sensing by Barkor/Atg14(L). PNAS 108:7769–74 [Google Scholar]
  98. Drin G, Casella JF, Gautier R, Boehmer T, Schwartz TU, Antonny B. 98.  2007. A general amphipathic α-helical motif for sensing membrane curvature. Nat. Struct. Mol. Biol. 14:138–46 [Google Scholar]
  99. Vanni S, Vamparys L, Gautier R, Drin G, Etchebest C. 99.  et al. 2013. Amphipathic lipid packing sensor motifs: probing bilayer defects with hydrophobic residues. Biophys. J. 104:575–84 [Google Scholar]
  100. Stack JH, DeWald DB, Takegawa K, Emr SD. 100.  1995. Vesicle-mediated protein transport: regulatory interactions between the Vps15 protein kinase and the Vps34 PtdIns 3-kinase essential for protein sorting to the vacuole in yeast. J. Cell Biol. 129:321–34 [Google Scholar]
  101. Cao Y, Wang Y, Saab WFA, Yang F, Pessin JE, Backer JM. 101.  2014. NRBF2 regulates macroautophagy as a component of Vps34 Complex I. Biochem. J. 461:315–22 [Google Scholar]
  102. Lu J, He L, Behrends C, Araki M, Araki K. 102.  et al. 2014. NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity. Nat. Commun. 5:3920 [Google Scholar]
  103. Zhong Y, Morris DH, Jin L, Patel MS, Karunakaran SK. 103.  et al. 2014. Nrfb2 suppresses autophagy by modulating Atg14L-containing Beclin 1-Vps34 protein complex architecture and reducting intracellular phosphatidylinositol-3 phosphate levels. J. Biol. Chem. 289:26021–37 [Google Scholar]
  104. Araki Y, Ku WC, Akioka M, May AI, Hayashi Y. 104.  et al. 2013. Atg38 is required for autophagy-specific phosphatidylinositol 3-kinase complex integrity. J. Cell Biol. 203:299–313 [Google Scholar]
  105. Ohashi Y, Soler N, Ortegon MG, Zhang L, Kirsten ML. 105.  et al. 2016. Characterization of Atg38 and NRBF2, a fifth subunit of the autophagic Vps34/PIKC3C complex. Autophagy 12:2129–44 [Google Scholar]
  106. Young LN, Cho K, Lawrence R, Zoncu R, Hurley JH. 106.  2016. Dynamics and architecture of the NRBF2-containing phosphatidylinositol 3-kinase complex I of autophagy. PNAS 113:8224–29 [Google Scholar]
  107. Oberstein A, Jeffrey PD, Shi YG. 107.  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 [Google Scholar]
  108. Pattingre S, Tassa A, Qu XP, Garuti R, Liang XH. 108.  et al. 2005. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–39 [Google Scholar]
  109. Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S. 109.  et al. 2007. Ambra1 regulates autophagy and development of the nervous system. Nature 447:1121–25 [Google Scholar]
  110. Xu DQ, Wang Z, Wang CY, Zhang DY, Wan HD. 110.  et al. 2016. PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity. EMBO J 35:496–514 [Google Scholar]
  111. Wei YJ, An ZY, Zou ZJ, Sumpter R, Su MF. 111.  et al. 2015. The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation. eLife 4:05289 [Google Scholar]
  112. Kim J, Kim YC, Fang C, Russell RC, Kim JH. 112.  et al. 2013. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152:290–303 [Google Scholar]
  113. Fujiwara N, Usui T, Ohama T, Sato K. 113.  2016. Regulation of Beclin 1 protein phosphorylation and autophagy by protein phosphatase 2A (PP2A) and death-associated protein kinase 3 (DAPK3). J. Biol. Chem. 291:10858–66 [Google Scholar]
  114. Wong PM, Feng Y, Wang JR, Shi R, Jiang XJ. 114.  2015. Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A. Nat. Commun. 6:8048 [Google Scholar]
  115. Zalckvar E, Berissi H, Mizrachy L, Idelchuk Y, Koren I. 115.  et al. 2009. DAP-kinase-mediated phosphorylation on the BH3 domain of Beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep 10:285–92 [Google Scholar]
  116. Wei YJ, Zou ZJ, Becker N, Anderson M, Sumpter R. 116.  et al. 2013. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 154:1269–84 [Google Scholar]
  117. Yuan HX, Russell RC, Guan KL. 117.  2013. Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy 9:1983–95 [Google Scholar]
  118. Wang RC, Wei YJ, An ZY, Zou ZJ, Xiao GH. 118.  et al. 2012. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338:956–59 [Google Scholar]
  119. Mari M, Griffith J, Rieter E, Krishnappa L, Klionsky DJ, Reggiori F. 119.  2010. An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis. J. Cell Biol. 190:1005–22 [Google Scholar]
  120. Yamamoto H, Kakuta S, Watanabe TM, Kitamura A, Sekito T. 120.  et al. 2012. Atg9 vesicles are an important membrane source during early steps of autophagosome formation. J. Cell Biol. 198:219–33 [Google Scholar]
  121. Graef M, Friedman JR, Graham C, Babu M, Nunnari J. 121.  2013. ER exit sites are physical and functional core autophagosome biogenesis components. Mol. Biol. Cell 24:2918–31 [Google Scholar]
  122. Ge L, Baskaran S, Schekman R, Hurley JH. 122.  2014. The protein-vesicle network of autophagy. Curr. Opin. Cell Biol. 29:18–24 [Google Scholar]
  123. Brandizzi F, Barlowe C. 123.  2013. Organization of the ER–Golgi interface for membrane traffic control. Nat. Rev. Mol. Cell Biol. 14:382–92 [Google Scholar]
  124. Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A. 124.  2009. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 11:1433–37 [Google Scholar]
  125. Yla-Anttila P, Vihinen H, Jokita E, Eskelinen E-L. 125.  2009. 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5:1180–85 [Google Scholar]
  126. Biazik J, Yla-Anttila P, Vihinen H, Jokitalo E, Eskelinen EL. 126.  2015. Ultrastructural relationship of the phagophore with surrounding organelles. Autophagy 11:439–51 [Google Scholar]
  127. Lang T, Reiche S, Straub M, Bredschneider M, Thumm M. 127.  2000. Autophagy and the cvt pathway both depend on AUT9. J. Bacteriol. 182:2125–33 [Google Scholar]
  128. Noda T, Kim J, Huang WP, Baba M, Tokunaga C. 128.  et al. 2000. Apg9p/Cvt7p is an integral membrane protein required for transport vesicle formation in the Cvt and autophagy pathways. J. Cell Biol. 148:465–79 [Google Scholar]
  129. He CC, Baba M, Cao Y, Klionsky DJ. 129.  2008. Self-interaction is critical for Atg9 transport and function at the phagophore assembly site during autophagy. Mol. Biol. Cell 19:5506–16 [Google Scholar]
  130. Puri C, Renna M, Bento CF, Moreau K, Rubinsztein DC. 130.  2013. Diverse autophagosome membrane sources coalesce in recycling endosomes. Cell 154:1285–99 [Google Scholar]
  131. Reggiori F, Tucker KA, Stromhaug PE, Klionsky DJ. 131.  2004. The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure. Dev. Cell 6:79–90 [Google Scholar]
  132. Young ARJ, Chan EYW, Hu XW, Koch R, Crawshaw SG. 132.  et al. 2006. Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J. Cell Sci. 119:3888–900 [Google Scholar]
  133. Geng JF, Nair U, Yasumura-Yorimitsu K, Klionsky DJ. 133.  2010. Post-Golgi Sec proteins are required for autophagy in Saccharomyces cerevisiae. Mol. Biol. Cell 21:2257–69 [Google Scholar]
  134. Shirahama-Noda K, Kira S, Yoshimori T, Noda T. 134.  2013. TRAPPIII is responsible for vesicular transport from early endosomes to Golgi, facilitating Atg9 cycling in autophagy. J. Cell Sci. 126:4963–73 [Google Scholar]
  135. Itakura E, Kishi-Itakura C, Koyama-Honda I, Mizushima N. 135.  2012. Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy. J. Cell Sci. 125:1488–99 [Google Scholar]
  136. Shintani T, Suzuki K, Kamada Y, Noda T, Ohsumi Y. 136.  2001. Apg2p functions in autophagosome formation on the perivacuolar structure. J. Biol. Chem. 276:30452–60 [Google Scholar]
  137. Wang CW, Kim J, Huang WP, Abeliovich H, Stromhaug PE. 137.  et al. 2001. Apg2 is a novel protein required for the cytoplasm to vacuole targeting, autophagy, and pexophagy pathways. J. Biol. Chem. 276:30442–51 [Google Scholar]
  138. Jin MY, He D, Backues SK, Freeberg MA, Liu X. 138.  et al. 2014. Transcriptional regulation by Pho23 modulates the frequency of autophagosome formation. Curr. Biol. 24:1314–22 [Google Scholar]
  139. Feng YC, Backues SK, Baba M, Heo JM, Harper JW, Klionsky DJ. 139.  2016. Phosphorylation of Atg9 regulates movement to the phagophore assembly site and the rate of autophagosome formation. Autophagy 12:648–58 [Google Scholar]
  140. Orsi A, Razi M, Dooley HC, Robinson D, Weston AE. 140.  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 [Google Scholar]
  141. Faini M, Beck R, Wieland FT, Briggs JAG. 141.  2013. Vesicle coats: structure, function, and general principles of assembly. Trends Cell Biol 23:279–88 [Google Scholar]
  142. Ishihara N, Hamasaki M, Yokota S, Suzuki K, Kamada Y. 142.  et al. 2001. Autophagosome requires specific early Sec proteins for its formation and NSF/SNARE for vacuolar fusion. Mol. Biol. Cell 12:3690–702 [Google Scholar]
  143. Wang J, Davis S, Menon S, Zhang JZ, Ding JZ. 143.  et al. 2015. Ypt1/Rab1 regulates Hrr25/CK1δ kinase activity in ER-Golgi traffic and macroautophagy. J. Cell Biol. 210:273–85 [Google Scholar]
  144. Lemus L, Ribas JL, Sikorska N, Goder V. 144.  2016. An ER-localized SNARE protein is exported in specific COPII vesicles for autophagosome biogenesis. Cell Rep 14:1710–22 [Google Scholar]
  145. Lynch-Day MA, Bhandari D, Menon S, Huang J, Cai HQ. 145.  et al. 2010. Trs85 directs a Ypt1 GEF, TRAPPIII, to the phagophore to promote autophagy. PNAS 107:7811–16 [Google Scholar]
  146. Tan D, Cai Y, Wang J, Zhang J, Menon S. 146.  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 [Google Scholar]
  147. Ge L, Melville D, Zhang M, Schekman R. 147.  2013. The ER–Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. eLife 2:e00947 [Google Scholar]
  148. Ge L, Zhang M, Schekman R. 148.  2014. Phosphatidylinositol 3-kinase and COPII generate LC3 lipidation vesicles from the ER-Golgi intermediate compartment. eLife 3:04135 [Google Scholar]
  149. Stadel D, Millarte V, Tillmann KD, Huber J, Tamin-Yecheskel BC. 149.  et al. 2015. TECPR2 cooperates with LC3C to regulate COPII-dependent ER export. Mol. Cell 60:89–104 [Google Scholar]
  150. Karanasios E, Walker SA, Okkenhaug H, Manifava M, Hummel E. 150.  et al. 2016. Autophagy initiation by ULK complex assembly on ER tubulovesicular regions marked by ATG9 vesicles. Nat. Commun. 7:12420 [Google Scholar]
  151. Hurley JH, Nogales E. 151.  2016. Next-generation electron microscopy in autophagy research. Curr. Opin. Struct. Biol. 41:211–16 [Google Scholar]
/content/journals/10.1146/annurev-biochem-061516-044820
Loading
Mechanisms of Autophagy Initiation
Annual Review of Biochemistry 86, 225 (2017); https://doi.org/10.1146/annurev-biochem-061516-044820
/content/journals/10.1146/annurev-biochem-061516-044820
/content/journals/10.1146/annurev-biochem-061516-044820
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error