Abstract
Autophagy is a catabolic intracellular process highly conserved among eukaryotes. During this process cytoplasmic material and organelles are surrounded and enclosed by double-membranes, forming vesicles called autophagosomes. Fusion of the autophagosomes with the lysosome/vacuole permits to expose the inner membrane compartment to lytic enzymes allowing the degradation of the engulfed cellular components. Autophagy has been shown to be an essential process for the cell survival in a multitude of situations. At a basal level, this catabolic pathway allows the removal of protein aggregates and/or damaged organelles to preserve the cell homeostasis. Under diverse pathological and physiological situations, the cell responds by increasing the levels of autophagy activity to cope with developmental adaptations or stresses. As a result, autophagy onset is observed in numerous diseases including neurodegenerative disorders, cancer, and myopathies. The cellular roles of autophagy as well as the function of the autophagy related (Atg) proteins have been extensively studied in the last decade and significant advances have been achieved. However, a multitude of questions still have to be answered before understanding the regulation and mechanism of autophagy in its full complexity. One of the enigmas in the field of autophagy is the origin of the lipid bilayers composing autophagosomes. While a considerable effort has been invested in solving this question during the past years, a consensus has not been reached yet. In this chapter, we discuss the studies, large part performed in yeast and mammalian cells, which propose several organelles of the eukaryotic cell including the endoplasmic reticulum (ER), Golgi, mitochondria, endosomes, and plasma membrane, as the source of autophagosomal membranes.
Susana Abreu and Jana Sanchez-Wandelmer have equally contributed to this chapter.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Arstila AU, Trump BF (1968) Studies on cellular autophagocytosis. The formation of autophagic vacuoles in the liver after glucagon administration. Am J Pathol 53(5):687–733
Axe EL et al (2008) Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182(4):685–701
de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456(7222):605–610
Dunn WA Jr (1990) Studies on the mechanisms of autophagy: formation of the autophagic vacuole. J Cell Biol 110(6):1923–1933
Dusetti NJ et al (2002) Cloning and expression of the rat vacuole membrane protein 1 (VMP1), a new gene activated in pancreas with acute pancreatitis, which promotes vacuole formation. Biochem Biophys Res Commun 290(2):641–649
Furuno K, Ishikawa T, Kato K (1982) Isolation and characterization of autolysosomes which appeared in rat liver after leupeptin treatment. J Biochem 91(6):1943–1950
Geng J et al (2010) Post-Golgi Sec proteins are required for autophagy in Saccharomyces cerevisiae. Mol Biol Cell 21(13):2257–2269
Gillooly DJ et al (2000) Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J 19(17):4577–4588
Hailey DW et al (2010) Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141(4):656–667
Hansen TE, Johansen T (2011) Following autophagy step by step. BMC Biol 9:39
Hayashi-Nishino M et al (2009) A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 11(12):1433–1437
He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93
Huang J, Klionsky DJ (2007) Autophagy and human disease. Cell Cycle 6(15):1837–1849
Ishihara N et al (2001) Autophagosome requires specific early Sec proteins for its formation and NSF/SNARE for vacuolar fusion. Mol Biol Cell 12(11):3690–3702
Itakura E, Mizushima N (2010) Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 6(6):764–776
Itakura E et al (2008) Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 19(12):5360–5372
Itakura E et al (2012) Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy. J Cell Sci 125(Pt 6):1488–1499
Itoh T et al (2008) Golgi-resident small GTPase Rab33B interacts with Atg16L and modulates autophagosome formation. Mol Biol Cell 19(7):2916–2925
Itoh T et al (2011) OATL1, a novel autophagosome-resident Rab33B-GAP, regulates autophagosomal maturation. J Cell Biol 192(5):839–853
Juhasz G, Neufeld TP (2006) Autophagy: a forty-year search for a missing membrane source. PLoS Biol 4(2):e36
Kageyama S et al (2011) The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella. Mol Biol Cell 22(13):2290–2300
Kim S, Naylor SA, DiAntonio A (2012) Drosophila Golgi membrane protein Ema promotes autophagosomal growth and function. Proc Natl Acad Sci USA 109(18):E1072–E1081
Klionsky DJ (2005) The molecular machinery of autophagy: unanswered questions. J Cell Sci 118(Pt 1):7–18
Kominami E et al (1983) Sequestration of cytoplasmic enzymes in an autophagic vacuole-Âlysosomal system induced by injection of leupeptin. J Biol Chem 258(10):6093–6100
Kornmann B et al (2009) An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science 325(5939):477–481
Liou W et al (1997) The autophagic and endocytic pathways converge at the nascent autophagic vacuoles. J Cell Biol 136(1):61–70
Locke M, Collins JV (1965) The structure and formation of protein granules in the fat body of an insect. J Cell Biol 26(3):857–884
Longatti A et al (2012) TBC1D14 regulates autophagosome formation via Rab11- and ULK1-Âpositive recycling endosomes. J Cell Biol 197(5):659–675
Lum JJ, DeBerardinis RJ, Thompson CB (2005) Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 6(6):439–448
Lynch-Day MA et al (2010) Trs85 directs a Ypt1 GEF, TRAPPIII, to the phagophore to promote autophagy. Proc Natl Acad Sci USA 107(17):7811–7816
Mari M et al (2010) An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis. J Cell Biol 190(6):1005–1022
Mari M, Tooze SA, Reggiori F (2011) The puzzling origin of the autophagosomal membrane. F1000 Biol Rep 3:25
Matsunaga K et al (2009) Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11(4):385–396
Matsunaga K et al (2010) Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. J Cell Biol 190(4):511–521
Mizushima N et al (2001) Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 152(4):657–668
Moreau K et al (2011) Autophagosome precursor maturation requires homotypic fusion. Cell 146(2):303–317
Moreau K et al (2012) Arf6 promotes autophagosome formation via effects on phosphatidylinositol 4,5-bisphosphate and phospholipase D. J Cell Biol 196(4):483–496
Munafo DB, Colombo MI (2002) Induction of autophagy causes dramatic changes in the subcellular distribution of GFP-Rab24. Traffic 3(7):472–482
Nakagawa I et al (2004) Autophagy defends cells against invading group A Streptococcus. Science 306(5698):1037–1040
Nakatogawa H, Ichimura Y, Ohsumi Y (2007) Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130(1):165–178
Nakatogawa H et al (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10(7):458–467
Noda T 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(3):465–480
Noda T et al (2012) Three-axis model for Atg recruitment in autophagy against Salmonella. Int J Cell Biol 2012:389562
Ohashi Y, Munro S (2010) Membrane delivery to the yeast autophagosome from the Golgi-Âendosomal system. Mol Biol Cell 21(22):3998–4008
Orsi A et al (2012) Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol Biol Cell 23(10):1860–1873
Polson HE et al (2010) Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy 6(4):506–522
Ravikumar B et al (2008) Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. J Cell Sci 121(Pt 10):1649–1660
Ravikumar B et al (2010) Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol 12(8):747–757
Reggiori F (2006) 1. Membrane origin for autophagy. Curr Top Dev Biol 74:1–30
Reggiori F, Tooze SA (2009) The EmERgence of autophagosomes. Dev Cell 17(6):747–748
Reggiori F et al (2004a) Early stages of the secretory pathway, but not endosomes, are required for Cvt vesicle and autophagosome assembly in Saccharomyces cerevisiae. Mol Biol Cell 15(5):2189–2204
Reggiori F et al (2004b) The Atg1–Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure. Dev Cell 6(1):79–90
Reggiori F et al (2012) Autophagy: more than a nonselective pathway. Int J Cell Biol 2012:219625
Rich KA, Burkett C, Webster P (2003) Cytoplasmic bacteria can be targets for autophagy. Cell Microbiol 5(7):455–468
Rubinsztein DC et al (2005) Dyneins, autophagy, aggregation and neurodegeneration. Autophagy 1(3):177–178
Stone SJ, Vance JE (2000) Phosphatidylserine synthase-1 and -2 are localized to mitochondria-Âassociated membranes. J Biol Chem 275(44):34534–34540
Suhy DA, Giddings TH Jr, Kirkegaard K (2000) Remodeling the endoplasmic reticulum by poliovirus infection and by individual viral proteins: an autophagy-like origin for virus-induced vesicles. J Virol 74(19):8953–8965
Suzuki K et al (2001) The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J 20(21):5971–5981
Suzuki K et al (2007) Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 12(2):209–218
Takahashi Y et al (2007) Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 9(10):1142–1151
Takahashi Y et al (2011) Bif-1 regulates Atg9 trafficking by mediating the fission of Golgi membranes during autophagy. Autophagy 7(1):61–73
Tian Y et al (2010) C. elegans screen identifies autophagy genes specific to multicellular organisms. Cell 141(6):1042–1055
Tooze SA (2010) The role of membrane proteins in mammalian autophagy. Semin Cell Dev Biol 21(7):677–682
Tooze SA, Yoshimori T (2010) The origin of the autophagosomal membrane. Nat Cell Biol 12(9):831–835
Tooze J et al (1990) In exocrine pancreas, the basolateral endocytic pathway converges with the autophagic pathway immediately after the early endosome. J Cell Biol 111(2):329–345
Ueno T, Muno D, Kominami E (1991) Membrane markers of endoplasmic reticulum preserved in autophagic vacuolar membranes isolated from leupeptin-administered rat liver. J Biol Chem 266(28):18995–18999
van der Vaart A, Reggiori F (2010) The Golgi complex as a source for yeast autophagosomal membranes. Autophagy 6(6):800–801
Vance JE (2008) Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J Lipid Res 49(7):1377–1387
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(4):573–580
Yamamoto H et al (2012) Atg9 vesicles are an important membrane source during early steps of autophagosome formation. J Cell Biol 198(2):219–233
Yla-Anttila P et al (2009) 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5(8):1180–1185
Yokota S (1993) Formation of autophagosomes during degradation of excess peroxisomes induced by administration of dioctyl phthalate. Eur J Cell Biol 61(1):67–80
Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12(Suppl 2):1542–1552
Young AR et al (2006) Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J Cell Sci 119(Pt 18):3888–3900
Acknowledgments
The authors thank Rene Scriwanek for the realization of the figures. F.R. is supported by the ECHO (700.59.003), ALW Open Program (821.02.017), and DFG-NWO cooperation (DN82-303) grants.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Abreu, S., Sanchez-Wandelmer, J., Reggiori, F. (2013). The Origin of Autophagosomes: The Beginning of an End. In: Wang, HG. (eds) Autophagy and Cancer. Current Cancer Research, vol 8. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6561-4_3
Download citation
DOI: https://doi.org/10.1007/978-1-4614-6561-4_3
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-6560-7
Online ISBN: 978-1-4614-6561-4
eBook Packages: MedicineMedicine (R0)