Autophagy in Nonmammalian Systems


Autophagy, or ‘self‐eating’, is a catabolic process that enables lysosome‐mediated degradation of cytoplasmic contents and recycling of macromolecules to be used in essential cellular processes. This process enables cells to survive during nutrient restriction, participates in cell death during development and functions in clearance of protein aggregates and intracellular pathogens. Autophagy has been widely studied in yeast, Drosophila and Caenorhabditis elegans, and studies in these organisms have revealed regulation by multiple cellular pathways. These include cell growth regulators, such as the Class I PI3 kinase and target of rapamycin (Tor), as well as cell death regulators, including caspases. Defects in autophagy are associated with neurodegeneration, pathogen infection, cancer and reduced lifespan. Genetic experiments in model organisms have been critical in determining how autophagy functions in health and disease.

Key Concepts

  • Over 30 atg genes have been shown to regulate autophagy.
  • Autophagy is induced in response to starvation and oxidative stress, enabling cells to recycle macromolecules and degrade damaged organelles.
  • Autophagy is required for steroid‐triggered removal of larval tissues during Drosophila melanogaster development.
  • Autophagosomes can sequester intracellular pathogens, which evade the cell's phagocytic machinery and traffic them to the lysosome for degradation.
  • Decreased autophagy leads to an inability to clear protein aggregates and mutant polyglutamine containing proteins from neurons in fly and worm neurodegeneration models.
  • Induction of autophagy in flies and worms can extend lifespan, whereas its block leads to increased neuronal cell death and reduced lifespan.
  • Autophagy has a context‐dependent role in tumourigenesis.

Keywords: autophagy; Drosophila; C. elegans; zebrafish; S. cerevisiae; neurodegeneration; ageing; cell death; lysosomes

Figure 1. Regulation of autophagy. (a) Steps of autophagy include the formation and expansion of the phagophore (also called isolation membrane) that gives rise to the autophagosome. In yeast, the PAS (phagophore assembling site, an organelle similar to the omegasome in mammalian cells) represents the place in which phagophore formation takes place, with the help of membranes coming from a multitude of organelles. Phagophore maturation and subsequent fusion with the lysosome generates a degradative organelles called autolysosome. Autophagosomes can also fuse with multivesicular endosomes to form amphisomes that eventually fuse with lysosomes. (b) Upon stress stimuli, such as starvation, specific Atg protein complexes are recruited to the PAS to form a phagophore in a hierarchical manner. The first complex is constituted by Atg11, Atg13, Atg17, Atg29 and Atg31 and Atg1, a protein kinase fundamental for autophagosome formation and viability during starvation. The interaction between Atg1 and Atg13 within the complex is either controlled by the serine/threonine kinase, target of rapamycin (TOR), 5' AMP‐activated protein kinase (AMPK) and the protein kinase A (PKA) or it is constitutive. In yeast, under nutrient‐rich conditions, TOR and PKA phosphorylate Atg13 in different sites, reducing its binding affinity for Atg1, while in response to nutrient starvation, TOR and PKA become inactivated, alleviating repression of Atg13. In addition, PKA also phosphorylates directly Atg1, or inhibits AMPK. Atg1 acts upstream of two conserved ubiquitin‐like conjugation pathways that are necessary for phagophore expansion. In particular, Atg7 was identified as an E1‐like enzyme that activates Atg12 and Atg8 in two distinct conjugation pathways. Atg12 and Atg8 are then covalently conjugated to the E2‐like proteins Atg10 and Atg3. This is followed by conjugation of Atg12 to Atg5 which together interact with Atg16. Atg16 acts in part as an E3 ligase for Atg8 lipidation with phosphatidylethanolamine (PE). The amount of Atg8 regulates the size of the autophagosome and Atg16 positive structures undergo a series of homotypic fusion events that expand the phagophore membrane. When a closed double membrane organelle is formed, the phagophore becomes an autophagosome. One of the last step of maturation is the Atg4‐dependent cleavage of Atg8‐PE (deconjugation), an event that triggers Atg12–Atg5–Atg16 complex disassembly. Atg positive autophagosomes are now ready to fuse their outer membrane with that of a lysosome and to release their content into the lysosomal lumen, where it will be degraded. Several other proteins regulating intracellular trafficking compartments also control autophagy. A first example of such dual use involves several vacuolar protein sorting (vps) proteins. First identified as Vps30, Atg6 was found to interact in two distinct complexes, both of which include the class III phosphatidylinositol (PI) kinase (PI3K), Vps34 and Vps15. A complex including Atg6 (in mammals Beclin1), Vps34, Vps15 (human P150) and Vps38 (human UVRAG) is required for vacuolar protein sorting, whereas a second complex containing Atg6, Vps34, Vps15 and Atg14 localises to the PAS and is required for autophagosome formation. In fact, Vps34 converts PI into PI(3)Phosphate (PtdIns3P), a modification that is key to recruitment Atg18, a component of the Atg9 complex, together with Atg2. The role of ESCRTs, SNAREs, HOPs, Tfeb and V‐ATPase as part of the LYNUS machinery in the autophagy process is discussed in detail in the text.


Artal‐Sanz M and Tavernarakis N (2009) Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans. Nature 461: 793–797.

Bakowski MA, Desjardins CA, Smelkinson MG, et al. (2014) Ubiquitin‐mediated response to microsporidia and virus infection in C. elegans. PLoS Pathogens 10: e1004200.

Bjedov I, Toivonen JM, Kerr F, et al. (2010) Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metabolism 11: 35–46.

Bouché V, Espinosa AP, Leone L, et al. (2016) Drosophila Mitf regulates the V‐ATPase and the lysosomal‐autophagic pathway. Autophagy 12: 484–498.

Chen Y and Dorn GW (2013) PINK1‐phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science (New York, NY). 340: 471–475.

Cianfanelli V, Fuoco C, Lorente M, et al. (2015) AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c‐Myc dephosphorylation and degradation. Nature Cell Biology 17: 20–30.

Cullup T, Kho AL, Dionisi‐Vici C, et al. (2013) Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nature Genetics 45: 83–87.

Demontis F and Perrimon N (2010) FOXO/4E‐BP signaling in Drosophila muscles regulates organism‐wide proteostasis during aging. Cell 143: 813–825.

DeVorkin L, Go NE, Hou Y‐CC, et al. (2014) The Drosophila effector caspase Dcp‐1 regulates mitochondrial dynamics and autophagic flux via SesB. The Journal of Cell Biology 205: 477–492.

Gomes LC, Odedra D, Dikic I and Pohl C (2016) Autophagy and modular restructuring of metabolism control germline tumor differentiation and proliferation in C. elegans. Autophagy 12: 529–546.

Guo B, Liang Q, Li L, et al. (2014) O‐GlcNAc‐modification of SNAP‐29 regulates autophagosome maturation. Nature Cell Biology 16: 1215–1226.

Gutierrez MG, Master SS, Singh SB, et al. (2004) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119: 753–766.

Itakura E, Kishi‐Itakura C and Mizushima N (2012) The hairpin‐type tail‐anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151: 1256–1269.

Juhász G, Erdi B, Sass M and Neufeld TP (2007) Atg7‐dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes & Development 21: 3061–3066.

Kirienko NV, Ausubel FM and Ruvkun G (2015) Mitophagy confers resistance to siderophore‐mediated killing by Pseudomonas aeruginosa. Proceedings of the National Academy of Sciences of the United States of America 112: 1821–1826.

Kuhn H, Sopko R, Coughlin M, Perrimon N and Mitchison T (2015) The Atg1‐Tor pathway regulates yolk catabolism in Drosophila embryos. Development (Cambridge, England) 142: 3869–3878.

Lapierre LR, De Magalhaes Filho CD, McQuary PR, et al. (2013) The TFEB orthologue HLH‐30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nature Communications 4: 2267.

Lee CY and Baehrecke EH (2001) Steroid regulation of autophagic programmed cell death during development. Development (Cambridge, England) 128: 1443–1455.

Lindmo K, Brech A, Finley KD, et al. (2008) The PI 3‐kinase regulator Vps15 is required for autophagic clearance of protein aggregates. Autophagy 4: 500–506.

Ma M, Zhao H, Zhao H, et al. (2016) Wildtype adult stem cells, unlike tumor cells, are resistant to cellular damages in Drosophila. Developmental Biology 411: 207–216.

Manzanillo PS, Ayres JS, Watson RO, et al. (2013) The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501: 512–516.

Mauvezin C, Nagy P, Juhász G and Neufeld TP (2015) Autophagosome–lysosome fusion is independent of V‐ATPase‐mediated acidification. Nature Communications 6: 1–14.

McPhee CK, Logan MA, Freeman MR and Baehrecke EH (2010) Activation of autophagy during cell death requires the engulfment receptor Draper. Nature 465: 1093–1096.

Morelli E, Ginefra P, Mastrodonato V, et al. (2014) Multiple functions of the SNARE protein Snap29 in autophagy, endocytic, and exocytic trafficking during epithelial formation in Drosophila. Autophagy 10: 2251–2268.

Nagy P, Varga A, Pircs K, Hegedus K and Juhász G (2013) Myc‐driven overgrowth requires unfolded protein response‐mediated induction of autophagy and antioxidant responses in Drosophila melanogaster. PLoS Genetics 9: e1003664.

Nair U, Jotwani A, Geng J, et al. (2011) SNARE proteins are required for macroautophagy. Cell 146: 290–302.

Nakamoto M, Moy RH, Xu J, et al. (2012) Virus recognition by Toll‐7 activates antiviral autophagy in Drosophila. Immunity 36: 658–667.

Nezis IP, Simonsen A, Sagona AP, et al. (2008) Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain. The Journal of Cell Biology 180: 1065–1071.

Nezis IP, Shravage BV, Sagona AP, et al. (2010) Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis. The Journal of Cell Biology 190: 523–531.

Ochaba J, Lukacsovich T, Csikos G, et al. (2014) Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proceedings of the National Academy of Sciences of the United States of America 111: 16889–16894.

Palikaras K, Lionaki E and Tavernarakis N (2015) Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521: 525–528.

Politi Y, Gal L, Kalifa Y, et al. (2014) Paternal mitochondrial destruction after fertilization is mediated by a common endocytic and autophagic pathway in Drosophila. Developmental Cell 29: 305–320.

Reggiori F and Klionsky DJ (2013) Autophagic processes in yeast: mechanism, machinery and regulation. Genetics 194: 341–361.

Rich KA, Burkett C and Webster P (2003) Cytoplasmic bacteria can be targets for autophagy. Cellular Microbiology 5: 455–468.

Rui Y‐N, Xu Z, Patel B, et al. (2015) Huntingtin functions as a scaffold for selective macroautophagy. Nature 17: 262–275.

Rusten TE, Lindmo K, Juhász G, et al. (2004) Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway. Developmental Cell 7: 179–192.

Rusten TE, Vaccari T, Lindmo K, et al. (2007) ESCRTs and Fab1 regulate distinct steps of autophagy. Current Biology 17: 1817–1825.

Scott RC, Schuldiner O and Neufeld TP (2004) Role and regulation of starvation‐induced autophagy in the Drosophila fat body. Developmental Cell 7: 167–178.

Shelly S, Lukinova N, Bambina S, Berman A and Cherry S (2009) Autophagy is an essential component of Drosophila immunity against vesicular stomatitis virus. Immunity 30: 588–598.

Shen W and Ganetzky B (2009) Autophagy promotes synapse development in Drosophila. The Journal of Cell Biology 187: 71–79.

Takáts S, Nagy P, Varga A, et al. (2013) Autophagosomal Syntaxin17‐dependent lysosomal degradation maintains neuronal function in Drosophila. The Journal of Cell Biology 201: 531–539.

Takats S, Pircs K, Nagy P, et al. (2014) Interaction of the HOPS complex with Syntaxin 17 mediates autophagosome clearance in Drosophila. Molecular Biology of the Cell 25: 1338–1354.

Tanner EA, Blute TA, Brachmann CB and McCall K (2011) Bcl‐2 proteins and autophagy regulate mitochondrial dynamics during programmed cell death in the Drosophila ovary. Development (Cambridge, England) 138: 327–338.

Tognon E, Kobia F, Busi I, et al. (2016) Control of lysosomal biogenesis and Notch‐dependent tissue patterning by components of the TFEB‐V‐ATPase axis in Drosophila melanogaster. Autophagy 12 (3): 499–514.

Winslow AR, Chen C‐W, Corrochano S, et al. (2010) α‐Synuclein impairs macroautophagy: implications for Parkinson's disease. The Journal of Cell Biology 190: 1023–1037.

Yano T, Mita S, Ohmori H, et al. (2008) Autophagic control of listeria through intracellular innate immune recognition in drosophila. Nature Immunology 9: 908–916.

Zhang T, Zhou Q, Ogmundsdottir MH, et al. (2015) Mitf is a master regulator of the v‐ATPase, forming a control module for cellular homeostasis with v‐ATPase and TORC1. Journal of Cell Science 128: 2938–2950.

Zirin J, Nieuwenhuis J and Perrimon N (2013) Role of autophagy in glycogen breakdown and its relevance to chloroquine myopathy. PLoS Biology 11: e1001708.

Zou C‐G, Ma Y‐C, Dai L‐L and Zhang K‐Q (2014) Autophagy protects C. elegans against necrosis during Pseudomonas aeruginosa infection. Proceedings of the National Academy of Sciences of the United States of America 111: 12480–12485.

Further Reading

Efeyan A, Zoncu R and Sabatini DM (2012) Amino acids and mTORC1: from lysosomes to disease. Trends in Molecular Medicine 18: 524–533.

Galluzzi L, Pietrocola F, Levine B and Kroemer G (2014) Metabolic control of autophagy. Cell 159: 1263–1276.

Moreau K, Renna M and Rubinsztein DC (2013) Connections between SNAREs and autophagy. Trends in Biochemical Sciences 38: 57–63.

Settembre C, Fraldi A, Medina DL and Ballabio A (2013) Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nature Reviews. Molecular Cell Biology 14: 283–296.

Tooze SA and Yoshimori T (2010) The origin of the autophagosomal membrane. Nature 12: 831–835.

White E (2012) Deconvoluting the context‐dependent role for autophagy in cancer. Nature Reviews. Cancer 12: 401–410.

Yang Z and Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nature 12: 814–822.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Mastrodonato, Valeria, Morelli, Elena, and Vaccari, Thomas(Nov 2016) Autophagy in Nonmammalian Systems. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021582.pub2]