Skip to main content

Advertisement

SpringerLink
Log in

Autophagosome formation in mammalian cells

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Autophagy is a fundamental intracellular trafficking pathway conserved from yeast to mammals. It is generally thought to play a pro-survival role, and it can be up regulated in response to both external and intracellular factors, including amino acid starvation, growth factor withdrawal, low cellular energy levels, endoplasmic reticulum (ER) stress, hypoxia, oxidative stress, pathogen infection, and organelle damage. During autophagy initiation a portion of the cytosol is surrounded by a flat membrane sheet known as the isolation membrane or phagophore. The isolation membrane then elongates and seals itself to form an autophagosome. The autophagosome fuses with normal endocytic traffic to mature into a late autophagosome, before fusing with lysosomes. The molecular machinery that enables formation of an autophagosome in response to the various autophagy stimuli is almost completely identified in yeast and—thanks to the observed conservation—is also being rapidly elucidated in higher eukaryotes including mammals. What are less clear and currently under intense investigation are the mechanism by which these various autophagy components co-ordinate in order to generate autophagosomes. In this review, we will discuss briefly the fundamental importance of autophagy in various pathophysiological states and we will then review in detail the various players in early autophagy. Our main thesis will be that a conserved group of heteromeric protein complexes and a relatively simple signalling lipid are responsible for the formation of autophagosomes in mammalian cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Klionsky DJ (2005) The molecular machinery of autophagy: unanswered questions. J Cell Sci 118:7–18

    Article  CAS  PubMed  Google Scholar 

  2. He C, Klionsky DJ (2009) Regulation Mechanisms and Signaling Pathways of Autophagy. Annu Rev Genet 43:67–93

    Article  CAS  PubMed  Google Scholar 

  3. Lum JJ, DeBerardinis RJ, Thompson CB (2005) Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 6:439–448

    Article  CAS  PubMed  Google Scholar 

  4. Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12(Suppl 2):1542–1552

    Article  CAS  PubMed  Google Scholar 

  5. Juhasz G, Neufeld TP (2006) Autophagy: a forty-year search for a missing membrane source. PLoS Biol 4:e36

    Article  PubMed  CAS  Google Scholar 

  6. Dunn WA Jr (1990) Studies on the mechanisms of autophagy: maturation of the autophagic vacuole. J Cell Biol 110:1935–1945

    Article  CAS  PubMed  Google Scholar 

  7. Klionsky DJ, Cregg JM, Dunn WA Jr, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y (2003) A unified nomenclature for yeast autophagy-related genes. Dev Cell 5:539–545

    Article  CAS  PubMed  Google Scholar 

  8. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889

    Article  CAS  PubMed  Google Scholar 

  9. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884

    Article  CAS  PubMed  Google Scholar 

  10. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075

    Article  CAS  PubMed  Google Scholar 

  11. Levine B, Deretic V (2007) Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol 7:767–777

    Article  CAS  PubMed  Google Scholar 

  12. Huang J, Klionsky DJ (2007) Autophagy and human disease. Cell Cycle 6:1837–1849

    Article  CAS  PubMed  Google Scholar 

  13. Orvedahl A, Alexander D, Talloczy Z, Sun Q, Wei Y, Zhang W, Burns D, Leib DA, Levine B (2007) HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1:23–35

    Article  CAS  PubMed  Google Scholar 

  14. Mathew R, Karantza-Wadsworth V, White E (2007) Role of autophagy in cancer. Nat Rev Cancer 7:961–967

    Article  CAS  PubMed  Google Scholar 

  15. Rameh LE, Cantley LC (1999) The role of phosphoinositide 3-kinase lipid products in cell function. J Biol Chem 274:8347–8350

    Article  CAS  PubMed  Google Scholar 

  16. Vanhaesebroeck B, Waterfield MD (1999) Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res 253:239–254

    Article  CAS  PubMed  Google Scholar 

  17. Falasca M, Maffucci T (2007) Role of class II phosphoinositide 3-kinase in cell signalling. Biochem Soc Trans 35:211–214

    Article  CAS  PubMed  Google Scholar 

  18. Ikonomov OC, Sbrissa D, Mlak K, Kanzaki M, Pessin J, Shisheva A (2002) Functional dissection of lipid and protein kinase signals of PIKfyve reveals the role of PtdIns 3, 5–P2 production for endomembrane integrity. J Biol Chem 277:9206–9211

    Article  CAS  PubMed  Google Scholar 

  19. Maehama T, Dixon JE (1999) PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 9:125–128

    Article  CAS  PubMed  Google Scholar 

  20. Clague MJ, Lorenzo O (2005) The myotubularin family of lipid phosphatases. Traffic 6:1063–1069

    Article  CAS  PubMed  Google Scholar 

  21. Vergne I, Roberts E, Elmaoued RA, Tosch V, Delgado MA, Proikas-Cezanne T, Laporte J, Deretic V (2009) Control of autophagy initiation by phosphoinositide 3-phosphatase jumpy. EMBO J 28:2244–2258

    Article  CAS  PubMed  Google Scholar 

  22. Taguchi-Atarashi N, Hamasaki M, Matsunaga K, Omori H, Ktistakis NT, Yoshimori T, Noda T (2010) Modulation of local PtdIns3P levels by the PI phosphatase MTMR3 regulates constitutive autophagy. Traffic 11:468–478

    Article  CAS  PubMed  Google Scholar 

  23. Konrad G, Schlecker T, Faulhammer F, Mayinger P (2002) Retention of the yeast Sac1p phosphatase in the endoplasmic reticulum causes distinct changes in cellular phosphoinositide levels and stimulates microsomal ATP transport. J Biol Chem 277:10547–10554

    Article  CAS  PubMed  Google Scholar 

  24. Burd CG, Emr SD (1998) Phosphatidylinositol(3)-phosphate signaling mediated by specific binding to RING FYVE domains. Mol Cell 2:157–162

    Article  CAS  PubMed  Google Scholar 

  25. Patki V, Lawe DC, Corvera S, Virbasius JV, Chawla A (1998) A functional PtdIns(3)P-binding motif. Nature 394:433–434

    Article  CAS  PubMed  Google Scholar 

  26. Overduin M, Cheever ML, Kutateladze TG (2001) Signaling with phosphoinositides: better than binary. Mol Interv 1:150–159

    CAS  PubMed  Google Scholar 

  27. Lindmo K, Stenmark H (2006) Regulation of membrane traffic by phosphoinositide 3-kinases. J Cell Sci 119:605–614

    Article  CAS  PubMed  Google Scholar 

  28. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484

    Article  CAS  PubMed  Google Scholar 

  29. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284:8023–8032

    Article  CAS  PubMed  Google Scholar 

  30. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303

    Article  CAS  PubMed  Google Scholar 

  31. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:1496–1501

    Article  CAS  PubMed  Google Scholar 

  32. Nada S, Hondo A, Kasai A, Koike M, Saito K, Uchiyama Y, Okada M (2009) The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes. EMBO J 28:477–489

    Article  CAS  PubMed  Google Scholar 

  33. Teis D, Taub N, Kurzbauer R, Hilber D, de Araujo ME, Erlacher M, Offterdinger M, Villunger A, Geley S, Bohn G, Klein C, Hess MW, Huber LA (2006) p14-MP1-MEK1 signaling regulates endosomal traffic and cellular proliferation during tissue homeostasis. J Cell Biol 175:861–868

    Article  CAS  PubMed  Google Scholar 

  34. Bohn G, Allroth A, Brandes G, Thiel J, Glocker E, Schaffer AA, Rathinam C, Taub N, Teis D, Zeidler C, Dewey RA, Geffers R, Buer J, Huber LA, Welte K, Grimbacher B, Klein C (2007) A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat Med 13:38–45

    Article  CAS  PubMed  Google Scholar 

  35. Roccio M, Bos JL, Zwartkruis FJ (2006) Regulation of the small GTPase Rheb by amino acids. Oncogene 25:657–664

    Article  CAS  PubMed  Google Scholar 

  36. Saito K, Araki Y, Kontani K, Nishina H, Katada T (2005) Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin. J Biochem 137:423–430

    Article  CAS  PubMed  Google Scholar 

  37. Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, Griffiths G, Ktistakis NT (2008) Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182:685–701

    Article  CAS  PubMed  Google Scholar 

  38. Futter CE, Collinson LM, Backer JM, Hopkins CR (2001) Human VPS34 is required for internal vesicle formation within multivesicular endosomes. J Cell Biol 155:1251–1264

    Article  CAS  PubMed  Google Scholar 

  39. Johnson EE, Overmeyer JH, Gunning WT, Maltese WA (2006) Gene silencing reveals a specific function of hVps34 phosphatidylinositol 3-kinase in late versus early endosomes. J Cell Sci 119:1219–1232

    Article  CAS  PubMed  Google Scholar 

  40. Obara K, Sekito T, Ohsumi Y (2006) Assortment of phosphatidylinositol 3-kinase complexes–Atg14p directs association of complex I to the pre-autophagosomal structure in Saccharomyces cerevisiae. Mol Biol Cell 17:1527–1539

    Article  CAS  PubMed  Google Scholar 

  41. Stein MP, Feng Y, Cooper KL, Welford AM, Wandinger-Ness A (2003) Human VPS34 and p150 are Rab7 interacting partners. Traffic 4:754–771

    Article  CAS  PubMed  Google Scholar 

  42. Backer JM (2008) The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J 410:1–17

    Article  CAS  PubMed  Google Scholar 

  43. Byfield MP, Murray JT, Backer JM (2005) hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 280:33076–33082

    Article  CAS  PubMed  Google Scholar 

  44. Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P, Byfield MP, Backer JM, Natt F, Bos JL, Zwartkruis FJ, Thomas G (2005) Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci USA 102:14238–14243

    Article  CAS  PubMed  Google Scholar 

  45. Wang RC, Levine B (2010) Autophagy in cellular growth control. FEBS Lett 584:1417–1426

    Article  CAS  PubMed  Google Scholar 

  46. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590

    Article  CAS  PubMed  Google Scholar 

  47. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226

    Article  CAS  PubMed  Google Scholar 

  48. Suzuki K, Ohsumi Y (2010) Current knowledge of the pre-autophagosomal structure (PAS). FEBS Lett 584:1280–1286

    Article  CAS  PubMed  Google Scholar 

  49. 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 20:5971–5981

    Article  CAS  PubMed  Google Scholar 

  50. Cheong H, Klionsky DJ (2008) Biochemical methods to monitor autophagy-related processes in yeast. Methods Enzymol 451:1–26

    Article  CAS  PubMed  Google Scholar 

  51. Xie Z, Nair U, Klionsky DJ (2008) Atg8 controls phagophore expansion during autophagosome formation. Mol Biol Cell 19:3290–3298

    Article  CAS  PubMed  Google Scholar 

  52. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10:458–467

    Article  CAS  PubMed  Google Scholar 

  53. Kabeya Y, Kamada Y, Baba M, Takikawa H, Sasaki M, Ohsumi Y (2005) Atg17 functions in cooperation with Atg1 and Atg13 in yeast autophagy. Mol Biol Cell 16:2544–2553

    Article  CAS  PubMed  Google Scholar 

  54. Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y (2000) Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150:1507–1513

    Article  CAS  PubMed  Google Scholar 

  55. Chan EY, Tooze SA (2009) Evolution of Atg1 function and regulation. Autophagy 5:758–765

    CAS  PubMed  Google Scholar 

  56. Hosokawa N, Sasaki T, Iemura S, Natsume T, Hara T, Mizushima N (2009) Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy 5:973–979

    Article  CAS  PubMed  Google Scholar 

  57. Mercer CA, Kaliappan A, Dennis PB (2009) A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy 5:649–662

    Article  CAS  PubMed  Google Scholar 

  58. Ganley IG, du Lam H, Wang J, Ding X, Chen S, Jiang X (2009) ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284:12297–12305

    Article  CAS  PubMed  Google Scholar 

  59. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, Kundu M, Kim DH (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20:1992–2003

    Article  CAS  PubMed  Google Scholar 

  60. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, Guan JL, Oshiro N, Mizushima N (2009) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20:1981–1991

    Article  CAS  PubMed  Google Scholar 

  61. Chan EY (2009) mTORC1 phosphorylates the ULK1-mAtg13-FIP200 autophagy regulatory complex, Sci Signal 2, pe51

  62. Mizushima N (2010) The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 22:132–139

    Article  CAS  PubMed  Google Scholar 

  63. He C, Baba M, Klionsky DJ (2009) Double duty of Atg9 self-association in autophagosome biogenesis. Autophagy 5:385–387

    Article  CAS  PubMed  Google Scholar 

  64. Sekito T, Kawamata T, Ichikawa R, Suzuki K, Ohsumi Y (2009) Atg17 recruits Atg9 to organize the pre-autophagosomal structure. Genes Cells 14:525–538

    Article  CAS  PubMed  Google Scholar 

  65. Young AR, Chan EY, Hu XW, Kochl R, Crawshaw SG, High S, Hailey DW, Lippincott-Schwartz J, Tooze SA (2006) Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J Cell Sci 119:3888–3900

    Article  CAS  PubMed  Google Scholar 

  66. Kuma A, Mizushima N, Ishihara N, Ohsumi Y (2002) Formation of the approximately 350-kDa Apg12-Apg5.Apg16 multimeric complex, mediated by Apg16 oligomerization, is essential for autophagy in yeast. J Biol Chem 277:18619–18625

    Article  CAS  PubMed  Google Scholar 

  67. Suzuki K, Kubota Y, Sekito T, Ohsumi Y (2007) Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 12:209–218

    Article  CAS  PubMed  Google Scholar 

  68. Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, Tokuhisa T, Ohsumi Y, Yoshimori T (2001) Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 152:657–668

    Article  CAS  PubMed  Google Scholar 

  69. Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, Inagaki F, Ohsumi Y (2007) The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem 282:37298–37302

    Article  CAS  PubMed  Google Scholar 

  70. Sou YS, Waguri S, Iwata J, Ueno T, Fujimura T, Hara T, Sawada N, Yamada A, Mizushima N, Uchiyama Y, Kominami E, Tanaka K, Komatsu M (2008) The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. Mol Biol Cell 19:4762–4775

    Article  CAS  PubMed  Google Scholar 

  71. Kihara A, Noda T, Ishihara N, 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

    Article  CAS  PubMed  Google Scholar 

  72. Obara K, Ohsumi Y (2008) Dynamics and function of PtdIns(3)P in autophagy. Autophagy 4:952–954

    CAS  PubMed  Google Scholar 

  73. Juhasz G, Hill JH, Yan Y, Sass M, Baehrecke EH, Backer JM, Neufeld TP (2008) The class III PI(3)K Vps34 promotes autophagy and endocytosis but not TOR signaling in Drosophila. J Cell Biol 181:655–666

    Article  CAS  PubMed  Google Scholar 

  74. Itakura E, Kishi C, Inoue K, Mizushima N (2008) Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 19:5360–5372

    Article  CAS  PubMed  Google Scholar 

  75. Petiot A, Ogier-Denis E, Blommaart EF, Meijer AJ, Codogno P (2000) Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 275:992–998

    Article  CAS  PubMed  Google Scholar 

  76. Wong J, Zhang J, Si X, Gao G, Mao I, McManus BM, Luo H (2008) Autophagosome supports coxsackievirus B3 replication in host cells. J Virol 82:9143–9153

    Article  CAS  PubMed  Google Scholar 

  77. Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelarova H, Meijer AJ (1997) The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 243:240–246

    Article  CAS  PubMed  Google Scholar 

  78. Eskelinen EL, Prescott AR, Cooper J, Brachmann SM, Wang L, Tang X, Backer JM, Lucocq JM (2002) Inhibition of autophagy in mitotic animal cells. Traffic 3:878–893

    Article  CAS  PubMed  Google Scholar 

  79. Miller S, Tavshanjian B, Oleksy A, Perisic O, Houseman BT, Shokat KM, Williams RL (2010) Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327:1638–1642

    Article  CAS  PubMed  Google Scholar 

  80. 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 121:1649–1660

    Article  CAS  PubMed  Google Scholar 

  81. Takatsuka C, Inoue Y, Matsuoka K, Moriyasu Y (2004) 3-methyladenine inhibits autophagy in tobacco culture cells under sucrose starvation conditions. Plant Cell Physiol 45:265–274

    Article  CAS  PubMed  Google Scholar 

  82. Gillooly DJ, Morrow IC, Lindsay M, Gould R, Bryant NJ, Gaullier JM, Parton RG, Stenmark H (2000) Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J 19:4577–4588

    Article  CAS  PubMed  Google Scholar 

  83. Walker S, Chandra P, Manifava M, Axe E, Ktistakis NT (2008) Making autophagosomes: localized synthesis of phosphatidylinositol 3-phosphate holds the clue. Autophagy 4:1093–1096

    CAS  PubMed  Google Scholar 

  84. 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 11:1433–1437

    Article  CAS  PubMed  Google Scholar 

  85. Yla-Anttila P, Vihinen H, Jokitalo E, and Eskelinen EL (2009) 3D tomography reveals connections between the phagophore and endoplasmic reticulum, Autophagy 5

  86. Hamasaki M, Yoshimori T (2010) Where do they come from? Insights into autophagosome formation. FEBS Lett 584:1296–1301

    Article  CAS  PubMed  Google Scholar 

  87. Stack JH, Herman PK, Schu PV, Emr SD (1993) A membrane-associated complex containing the Vps15 protein kinase and the Vps34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole. EMBO J 12:2195–2204

    CAS  PubMed  Google Scholar 

  88. Stack JH, Emr SD (1994) Vps34p required for yeast vacuolar protein sorting is a multiple specificity kinase that exhibits both protein kinase and phosphatidylinositol-specific PI 3-kinase activities. J Biol Chem 269:31552–31562

    CAS  PubMed  Google Scholar 

  89. Burda P, Padilla SM, Sarkar S, Emr SD (2002) Retromer function in endosome-to-Golgi retrograde transport is regulated by the yeast Vps34 PtdIns 3-kinase. J Cell Sci 115:3889–3900

    Article  CAS  PubMed  Google Scholar 

  90. Yan Y, Flinn RJ, Wu H, Schnur RS, Backer JM (2009) hVps15, but not Ca2+/CaM, is required for the activity and regulation of hVps34 in mammalian cells. Biochem J 417:747–755

    Article  CAS  PubMed  Google Scholar 

  91. Lindmo K, Brech A, Finley KD, Gaumer S, Contamine D, Rusten TE, Stenmark H (2008) The PI 3-kinase regulator Vps15 is required for autophagic clearance of protein aggregates. Autophagy 4:500–506

    CAS  PubMed  Google Scholar 

  92. Furuya N, Yu J, Byfield M, Pattingre S, Levine B (2005) The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy 1:46–52

    Article  CAS  PubMed  Google Scholar 

  93. Yan Y, Backer JM (2007) Regulation of class III (Vps34) PI3Ks. Biochem Soc Trans 35:239–241

    Article  CAS  PubMed  Google Scholar 

  94. Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B (1998) Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 72:8586–8596

    CAS  PubMed  Google Scholar 

  95. 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 119:259–270

    Article  CAS  PubMed  Google Scholar 

  96. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672–676

    Article  CAS  PubMed  Google Scholar 

  97. Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, Corazzari M, Fuoco C, Ucar A, Schwartz P, Gruss P, Piacentini M, Chowdhury K, Cecconi F (2007) Ambra1 regulates autophagy and development of the nervous system. Nature 447:1121–1125

    CAS  PubMed  Google Scholar 

  98. Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA, Geneste O, Kroemer G (2007) BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy 3:374–376

    CAS  PubMed  Google Scholar 

  99. He C, Levine B (2010) The Beclin 1 interactome. Curr Opin Cell Biol 22:140–149

    Article  CAS  PubMed  Google Scholar 

  100. Levine B, Sinha S, Kroemer G (2008) Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 4:600–606

    CAS  PubMed  Google Scholar 

  101. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939

    Article  CAS  PubMed  Google Scholar 

  102. Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P, Tasdemir E, Pierron G, Troulinaki K, Tavernarakis N, Hickman JA, Geneste O, Kroemer G (2007) Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 26:2527–2539

    Article  CAS  PubMed  Google Scholar 

  103. Wei Y, Pattingre S, Sinha S, Bassik M, Levine B (2008) JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30:678–688

    Article  CAS  PubMed  Google Scholar 

  104. Shimizu S, Konishi A, Nishida Y, Mizuta T, Nishina H, Yamamoto A, Tsujimoto Y (2010) Involvement of JNK in the regulation of autophagic cell death. Oncogene 29:2070–2082

    Article  CAS  PubMed  Google Scholar 

  105. Zalckvar E, Berissi H, Eisenstein M, Kimchi A (2009) Phosphorylation of Beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with Bcl-2 and Bcl-XL. Autophagy 5:720–722

    Article  CAS  PubMed  Google Scholar 

  106. Zalckvar E, Berissi H, Mizrachy L, Idelchuk Y, Koren I, Eisenstein M, Sabanay H, Pinkas-Kramarski R, Kimchi A (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 10:285–292

    Article  CAS  PubMed  Google Scholar 

  107. Chang NC, Nguyen M, Germain M, Shore GC (2010) Antagonism of Beclin 1-dependent autophagy by BCL-2 at the endoplasmic reticulum requires NAF-1. EMBO J 29:606–618

    Article  CAS  PubMed  Google Scholar 

  108. Maiuri MC, Criollo A, Kroemer G (2010) Crosstalk between apoptosis and autophagy within the Beclin 1 interactome. EMBO J 29:515–516

    Article  CAS  PubMed  Google Scholar 

  109. Itakura E, Mizushima N (2009) Atg14 and UVRAG: mutually exclusive subunits of mammalian Beclin 1-PI3K complexes. Autophagy 5:534–536

    Article  CAS  PubMed  Google Scholar 

  110. Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH, Jung JU (2006) Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 8:688–699

    Article  CAS  PubMed  Google Scholar 

  111. Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, Vergne I, Deretic V, Feng P, Akazawa C, Jung JU (2008) Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 10:776–787

    Article  CAS  PubMed  Google Scholar 

  112. Funderburk SF, Wang QJ, and Yue Z (2010) The Beclin 1-VPS34 complex - at the crossroads of autophagy and beyond, Trends Cell Biol

  113. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura T, Isobe T, Akira S, Noda T, Yoshimori T (2009) Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11:385–396

    Article  CAS  PubMed  Google Scholar 

  114. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, Heintz N, Yue Z (2009) Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 11:468–476

    Article  CAS  PubMed  Google Scholar 

  115. Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, Liang C, Jung JU, Cheng JQ, Mule JJ, Pledger WJ, Wang HG (2007) Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 9:1142–1151

    Article  CAS  PubMed  Google Scholar 

  116. Takahashi Y, Meyerkord CL, Wang HG (2008) BARgaining membranes for autophagosome formation: Regulation of autophagy and tumorigenesis by Bif-1/Endophilin B1. Autophagy 4:121–124

    CAS  PubMed  Google Scholar 

  117. Takahashi Y, Karbowski M, Yamaguchi H, Kazi A, Wu J, Sebti SM, Youle RJ, Wang HG (2005) Loss of Bif-1 suppresses Bax/Bak conformational change and mitochondrial apoptosis. Mol Cell Biol 25:9369–9382

    Article  CAS  PubMed  Google Scholar 

  118. Christoforidis S, Miaczynska M, Ashman K, Wilm M, Zhao L, Yip SC, Waterfield MD, Backer JM, Zerial M (1999) Phosphatidylinositol-3-OH kinases are Rab5 effectors. Nat Cell Biol 1:249–252

    Article  CAS  PubMed  Google Scholar 

  119. Ravikumar B, Duden R, Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11:1107–1117

    Article  CAS  PubMed  Google Scholar 

  120. Audhya A, Desai A, Oegema K (2007) A role for Rab5 in structuring the endoplasmic reticulum. J Cell Biol 178:43–56

    Article  CAS  PubMed  Google Scholar 

  121. Hoyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T, Bianchi K, Fehrenbacher N, Elling F, Rizzuto R, Mathiasen IS, Jaattela M (2007) Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 25:193–205

    Article  PubMed  CAS  Google Scholar 

  122. Brady NR, Hamacher-Brady A, Yuan H, Gottlieb RA (2007) The autophagic response to nutrient deprivation in the hl-1 cardiac myocyte is modulated by Bcl-2 and sarco/endoplasmic reticulum calcium stores. FEBS J 274:3184–3197

    Article  PubMed  CAS  Google Scholar 

  123. Gulati P, Gaspers LD, Dann SG, Joaquin M, Nobukuni T, Natt F, Kozma SC, Thomas AP, Thomas G (2008) Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab 7:456–465

    Article  CAS  PubMed  Google Scholar 

  124. Krick R, Henke S, Tolstrup J, Thumm M (2008) Dissecting the localization and function of Atg18, Atg21 and Ygr223c. Autophagy 4:896–910

    CAS  PubMed  Google Scholar 

  125. Stromhaug PE, Reggiori F, Guan J, Wang CW, Klionsky DJ (2004) Atg21 is a phosphoinositide binding protein required for efficient lipidation and localization of Atg8 during uptake of aminopeptidase I by selective autophagy. Mol Biol Cell 15:3553–3566

    Article  CAS  PubMed  Google Scholar 

  126. Polson HE, de Lartigue J, Rigden DJ, Reedjik M, Urbe S, Clague MJ, and Tooze SA (2010) Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation, Autophagy 6

  127. Jeffries TR, Dove SK, Michell RH, Parker PJ (2004) PtdIns-specific MPR pathway association of a novel WD40 repeat protein, WIPI49. Mol Biol Cell 15:2652–2663

    Article  CAS  PubMed  Google Scholar 

  128. Simonsen A, Birkeland HC, Gillooly DJ, Mizushima N, Kuma A, Yoshimori T, Slagsvold T, Brech A, Stenmark H (2004) Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes. J Cell Sci 117:4239–4251

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

Work in our laboratory is supported by the Biotechnology and Biological Sciences Research Council (BBSRC).

Author information

Authors and Affiliations

  1. Signalling Programme, Babraham Institute, Cambridge, CB22 3AT, UK

    Chloe Burman & Nicholas T. Ktistakis

Authors
  1. Chloe Burman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas T. Ktistakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chloe Burman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burman, C., Ktistakis, N.T. Autophagosome formation in mammalian cells. Semin Immunopathol 32, 397–413 (2010). https://doi.org/10.1007/s00281-010-0222-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-010-0222-z

Keywords

Search

Navigation